Pyrimidine derivatives for treatment of hyperproliferative disorders

ABSTRACT

Pyrimidine derivatives of formula (I) 
     
       
         
         
             
             
         
       
     
     in which J and Y represent aromatic or heteroaromatic rings; R 2 , G, G′, and G″ represent substituent groups and R 2a  represents H or halogen; L represents a linking group; and M represents CH or N. Pharmaceutical compositions containing these compounds, and methods of using these compounds in treatment of hyperproliferative diseases such as cancer are also disclosed and claimed.

This application is a continuation-in-part-application of InternationalApplication No. PCT/US2004/033430, filed on Aug. 10, 2004, claiming thebenefit of U.S. Ser. No. 60/510,804, filed on Oct. 10, 2003, both ofwhich are hereby incorporated by reference.

FIELD

This application relates to small molecule heterocyclic pharmaceuticals,and more particularly, to amino-substituted pyrimidine derivativeshaving cytotoxic activity.

BACKGROUND

Nitrogen-containing heterocycles such as pyrimidine derivatives havebeen disclosed in patent and non-patent publications as having a varietyof pharmaceutical properties and utilities. Several such publicationsare listed below.

WO 03/062225 (Bayer) relates to pyrimidine derivatives as rho-kinaseinhibitors, and their use in treatment of rho-kinase mediated conditionsincluding cancer.

WO 2001/87845 (Fujisawa) relates to N-containing heterocyclic compoundshaving 5-HT antagonistic activity. These compounds are stated as beinguseful for treating or preventing central nervous system disorders.

WO 95/10506 (Du Pont Merck) relates to 1N-alkyl-N-arylpyrimidinaminesand derivatives thereof, which are stated to inhibit the corticopropinreleasing factor (CRF) peptide and to be useful for treatment ofpsychiatric disorders and neurological diseases.

WO 2004/048365 (Chiron) relates to 2,4,6-trisubstituted pyrimidines asphosphotidylinositol (PI) 3-kinase inhibitors and their use in treatmentof cancer.

WO 2004/000820 (Cellular Genomics) relates to N-containing heterocyclesand other compounds as kinase modulators, and their use in treatment ofnumerous kinase-associated disorders including cancer.

WO 01/62233 (Hoffmann La Roche) relates to nitrogen-containingheterocycles and their use in treatment of diseases modulated by theadenosine receptor.

US 2004/0097504 (Vertex) relates to nitrogen-containing heterocyclesuseful in treatment of various protein kinase-mediated disorders.

The pharmaceutical field is always interested in identifying newpharmaceutically active compounds. Such materials are the subject of thepresent application.

Compounds of the Invention

In a first embodiment, this invention relates to compounds of Formula(I)

wherein

-   R¹ represents H, (C₁-C₃)alkyl, or cyclopropyl;-   R² represents (C₁-C₃)alkyl, cyclopropyl, O(C₁-C₃)alkyl, or NR³R⁴    wherein R³ and R⁴ are H, (C₁-C₃)alkyl, or cyclopropyl;-   R^(2a) represents H or halogen;-   M represents CH or N;-   L represents a carbonyl group, O, NR⁵, CR⁶R⁷, or (C₂-C₃)alkylenyl    which is optionally substituted up to twice by groups independently    selected from halogen and OH; wherein    -   R⁵ is H or (C₁-C₃)alkyl; and    -   R⁶ and R⁷ are independently H, CH₃, halogen, or OH;-   J represents an aromatic or heteroaromatic ring selected from the    group consisting of

-   Y represents an aromatic or heteroaromatic ring selected from the    group consisting of

-   -   wherein R⁸ represents H or (C₁-C₃)alkyl;

-   G″ represents a substituent selected from the group consisting of    (C₁-C₃)alkyl, cyclopropyl, O(C₁-C₃)alkyl, halogen, CF₃, CN and    CO₂R⁹;    -   wherein    -   R⁹ represents H or (C₁-C₃)alkyl; and

-   m represents the number of substituents G″, and is 0, 1, or 2;

-   G represents a substituent located on ring J;

-   G′ represents a substituent located on ring Y;

-   n represents the number of substituents G; and

-   n′ represents the number of substituents G′;

-   n and n′ are independently 0, 1, 2, or 3, subject to the provisos    that    -   1) ring J and ring Y each may be substituted independently up to        3 times by substituents listed below as numbers G1-G2, to a        maximum total of 4 substituents on rings J and Y,    -   2) ring J and ring Y each may be substituted independently up to        2 times by substituents listed below as numbers G3-G11, to a        maximum total of 3 substituents on rings J and Y, and    -   3) ring J and ring Y each may be substituted independently once        by a substituent selected from those listed below as numbers        G12-G37;

-   and subject to the further provisos    -   4) when J is phenyl, G is other than OH or alkylthio; and when J        is phenyl or pyridyl, n is 1, 2, or 3;    -   5) when J is phenyl, and G is G4 shown below, then R² is NR³R⁴;

-   G and G′ moieties are independently selected from the group    consisting of:    -   G1) halogen;    -   G2) O(C₁-C₄)alkyl which optionally is substituted up to two        times by O(C₁-C₂)alkyl;    -   G3) OH;    -   G4) (C₁-C₅)alkyl, which is optionally substituted independently        up to two times by groups selected from hydroxyl and cyano, or        up to three times by halogen;    -   G5) OCF₃;    -   G6) NHC(O)(C₁-C₃)alkyl;    -   G7) NHSO₂(C₁-C₃)alkyl;    -   G8) NR¹⁰R¹¹, wherein        -   R¹⁰ and R¹¹ are independently selected from        -   H,        -   CH₃,        -   cyclopropyl,        -   benzyl,        -   NR¹²R¹³ wherein            -   R¹² and R¹³ are independently H or (C₁-C₃)alkyl,                provided that both R¹⁰ and R¹¹ are not NR¹²R¹³                simultaneously, and        -   (C₂-C₄)alkyl which is optionally substituted up to three            times by halogen, and up to two times by substituent groups            independently selected from hydroxyl, O(C₁-C₃)alkyl, and            NR¹⁴R¹⁵, wherein            -   R¹⁴ and R¹⁵ are independently H or (C₁-C₃)alkyl, or            -   R¹⁴ and R¹⁵ can join to form a heterocycle of formula

-   -   -   -    wherein                -   Q represents CH₂, O, or NR¹⁶, and                -   R¹⁶ represents H or (C₁-C₃)alkyl, or

        -   R¹⁰ and R¹¹ may be joined to form a saturated 5-6-membered            N-containing ring which is optionally substituted up to two            times by            -   OH,            -   NR¹⁷R¹⁸, wherein                -   R¹⁷ and R¹⁸ are H or (C₁-C₃)alkyl, or by            -   (C₁-C₃)alkyl which is optionally substituted up to two                times by halogen, OH, or O(C₁-C₃)alkyl;

    -   G9) (CH₂)_(a)—NR¹⁹R²⁰ wherein        -   R¹⁹ and R²⁰ are independently H, (C₁-C₅)alkyl, or            (C₃-C₆)cycloalkyl, or may be joined to form a saturated            5-6-membered N-containing ring; and        -   the subscript “a” is an integer of 1-4;

    -   G10)

-   -    wherein        -   Q′ is O or NR²¹;        -   R²¹ is H, (C₁-C₃)alkyl, or cyclopropyl; and        -   the subscript “b” is an integer of 1-3;    -   G11) CH₂NR²²(CH₂)_(c)OCH₃ wherein        -   R²² is H, (C₁-C₃)alkyl, or cyclopropyl; and        -   the subscript “c” is an integer of 2-4;    -   G12) OSO₂NR²³R²⁴ wherein        -   R²³ and R²⁴ independently represent H, CH₃, or (C₂-C₄)alkyl            which may optionally be substituted once by OH or NR²⁵R²⁶,            wherein            -   R²⁵ and R²⁶ independently represent H or (C₁-C₃)alkyl;    -   G13) CN;    -   G14) NO₂;    -   G15) cyclopropyl;    -   G16) OR²⁷, wherein        -   R²⁷ represents phenyl or benzyl;    -   G17) S(C₁-C₃)alkyl;    -   G18) CH═CH—(CH₂)₁₋₃—OR⁵; wherein        -   R⁵ represents H or (C₁-C₃)alkyl;    -   G19)

-   -   G20)

-   -   G21) C(O)NR²⁸R²⁹, wherein        -   R²⁸ and R²⁹ are independently selected from H,        -   cyclopropyl, provided that both R²⁸ and R²⁹ are not            simultaneously cyclopropyl,

-   -   -    provided that this group does not constitute both R²⁸ and            R²⁹ simultaneously, and        -   (C₁-C₃)alkyl which is optionally substituted up to two times            by OH; or        -   R²⁸ and R²⁹ may be joined to form a saturated 5-6-membered            N-containing ring which is optionally substituted up to two            times by OH, or by (C₁-C₃)alkyl which in turn is optionally            substituted up to two times by OH or O(C₁-C₃)alkyl;

    -   G22)

-   -    wherein        -   Q″ is O or NR³⁰, and        -   R³⁰ is            -   H,            -   cyclopropyl, or            -   (C₁-C₃)alkyl which is optionally substituted once by                halogen, OH, or O(C₁-C₃)alkyl;    -   G23) O—(CH₂)_(d)—NR³¹R³² wherein        -   R³¹ and R³² are independently H, (C₁-C₃)alkyl, or            cyclopropyl, or may be joined to form a saturated            5-6-membered N-containing ring; and        -   the subscript “d” is an integer of 2-4;    -   G24)

-   -    wherein        -   the subscript “e” is an integer of 2-3; and        -   Q′″ is O or NR³³; and        -   R³³ is H, (C₁-C₃)alkyl, or cyclopropyl;    -   G25)

-   -    wherein        -   Q^(iv) is O or NR³⁴; and        -   R³⁴ is H, (C₁-C₃)alkyl, or cyclopropyl;    -   G26) C(O)NR³⁵(CH₂)_(f)OR³⁶ wherein        -   R³⁵ is H, (C₁-C₃)alkyl, or cyclopropyl;        -   R³⁶ is (C₁-C₆)alkyl optionally substituted up to two times            by halogen, OH, or O(C₁-C₃)alkyl, and        -   the subscript “f” is an integer of 2-4;    -   G27) CO₂R³⁷ wherein        -   R³⁷ is H or (C₁-C₃)alkyl;    -   G28) phenyl, which is optionally substituted by up to 2 groups        selected from halogen, (C₁-C₃)alkyl, OR³⁸, CN, CF₃, and NR³⁹R⁴⁰        -   wherein            -   R³⁸ represents H or (C₁-C₃)alkyl; and            -   R³⁹ and R⁴⁰ represent H or (C₁-C₃)alkyl;    -   G29) NR⁴¹SO₂NR⁴²R⁴³ wherein        -   R⁴¹ represents H, or (C₁-C₄)alkyl, and        -   R⁴² and R⁴³ independently represent H, CH₃, or (C₂-C₃)alkyl            which may optionally be substituted once by —OH or NR⁴⁴R⁴⁵,            wherein            -   R⁴⁴ and R⁴⁵ independently represent H or (C₁-C₃)alkyl;    -   G30) OC(O)—CH₂—NR⁴⁶R⁴⁷ wherein        -   R⁴⁶ and R⁴⁷ independently represent H, (C₁-C₃)alkyl, or            CO₂(t-butyl), provided that R⁴⁶ and R⁴⁷ are not both            simultaneously CO₂(t-butyl);    -   G31) N(R⁴⁸)C(O)R⁴⁹ wherein        -   R⁴⁸ (represents H or (C₁-C₃)alkyl; and        -   R⁴⁹ represents            -   (CH₂)₁₋₃—CO₂H,            -   O(C₂-C₄)alkyl,            -   (CH₂)₁₋₄—NR⁵⁰R⁵¹ wherein                -   R⁵⁰ and R⁵¹ independently represent H or                    (C₁-C₃)alkyl, or            -   CH(R⁵²)—NR⁵³R⁵⁴ wherein                -   R⁵² represents (CH₂)₁₋₄—NH₂, CH₂OH, CH(CH₃)OH, or                    (C₁-C₃)alkyl; and                -   R⁵³ and R⁵⁴ independently represent H or                    (C₁-C₃)alkyl;    -   G32) C(O)—(C₁-C₃)alkyl;    -   G33) (CH₂)_(g)—N(R⁵⁵)—C(O)—R⁵⁶ wherein        -   g represents 1, 2, or 3;        -   R⁵⁵ represents H or (C₁-C₃)alkyl;        -   R⁵⁶ represents            -   (C₁-C₃)alkyl optionally substituted up to two times by                OR⁵⁷ or NR⁵⁸R⁵⁹, wherein                -   R⁵⁷ represents H or (C₁-C₃)alkyl, and                -   R⁵⁸ and R⁵⁹ each represents H or (C₁-C₃)alkyl,        -   or R⁵⁶ represents

-   -   -    wherein            -   R⁶⁰ represents halogen, (C₁-C₃)alkyl, O(C₁-C₃)alkyl, CN,                OH, CF₃, or NR⁶¹R⁶², wherein                -   R⁶¹ and R⁶² represent H or (C₁-C₃)alkyl; and            -   h represents 0, 1, or 2;

    -   G34) (CH₂)_(i)—N(R⁶³)—C(O)—NR⁶⁴R⁶⁵ wherein        -   i represents 1, 2, or 3;        -   R⁶³ represents H or (C₁-C₃)alkyl;        -   R⁶⁴ and R⁶⁵ each represents H or (C₁-C₃)alkyl; or        -   R⁶⁴ and R⁶⁵ may be joined to form

-   -   -    wherein            -   Q^(V) represents CH₂, O or NR⁶⁶ wherein                -   R⁶⁶ represents H or (C₁-C₃)alkyl;

    -   G35)

-   -    wherein        -   j represents 1, 2, or 3;        -   R⁶⁷ represents H or (C₁-C₃)alkyl; and        -   R⁶⁸ represents H or (C₁-C₃)alkyl;    -   G36) (CH₂)_(k)—N(R⁶⁹)—SO₂—R⁷⁰ wherein        -   k represents 1, 2, or 3;        -   R⁶⁹ represents H or (C₁-C₃)alkyl; and        -   R⁷⁹ represents (C₁-C₄)alkyl, or phenyl which is optionally            substituted up to perhalo by halogen or up to three times by            OR⁷¹, CN, CF₃, or NR⁷²R⁷³, wherein            -   R⁷¹ represents H or (C₁-C₃)alkyl; and            -   R⁷² and R⁷³ each represents H or (C₁-C₃)alkyl;    -   G37) CH═CH—(CH₂)₁₋₃—NR⁷⁴R⁷⁵ wherein        -   R⁷⁴ and R⁷⁵ represent H or (C₁-C₃)alkyl;

-   or a pharmaceutically acceptable salt, solvate, solvate of a salt,    or stereoisomer thereof.

In a second embodiment, the invention relates to a compound of the abovefirst embodiment, having the structure

-   wherein the definitions of the variables are as given above in the    first embodiment, except that in this second embodiment-   R¹ represents H;-   M represents CH;-   J represents a heteroaromatic ring selected from the group    consisting of

-   Y represents an aromatic or heteroaromatic ring selected from the    group consisting of

-   n and n′ are independently 0, 1, 2, or 3, subject to the provisos    that    -   1) ring J and ring Y each may be substituted independently up to        3 times by substituents listed below as numbers G1-G2, to a        maximum total of 4 substituents on rings J and Y,    -   2) ring J and ring Y each may be substituted independently up to        2 times by substituents listed below as numbers G3-G5 and G8, to        a maximum total of 3 substituents on rings J and Y, and    -   3) ring J and ring Y each may be substituted independently once        by a substituent selected from those listed below as numbers        G12, G13, G22, G29, and G31;-   and subject to the further proviso    -   4) when J is pyridyl, n is 1, 2, or 3;-   and proviso 5 does not apply;-   G and G′ moieties are independently selected from the group    consisting of:    -   G1) halogen;    -   G2) O(C₁-C₄)alkyl which optionally is substituted up to two        times by O(C₁-C₂)alkyl;    -   G3) OH;    -   G4) (C₁-C₅)alkyl, which is optionally substituted independently        up to two times by groups selected from hydroxyl and cyano, or        up to three times by halogen;    -   G5) OCF₃;    -   G8) NR¹⁰R¹¹, wherein        -   R¹⁰ and R¹¹ are independently selected from            -   H,            -   CH₃,            -   cyclopropyl,            -   benzyl,            -   NR¹²R¹³ wherein                -   R¹² and R¹³ are independently H or (C₁-C₃)alkyl,                    provided that both R¹⁰ and R¹¹ are not NR¹²R¹³                    simultaneously, and            -   (C₂-C₄)alkyl which is optionally substituted up to three                times by halogen, and up to two times by substituent                groups independently selected from hydroxyl,                O(C₁-C₃)alkyl, and NR¹⁴R¹⁵, wherein            -   R¹⁴ and R¹⁵ are independently H or (C₁-C₃)alkyl, or                -   R¹⁴ and R¹⁵ can join to form a heterocycle of                    formula

-   -   -   -   -    wherein                -    Q represents CH₂, O, or NR¹⁶, and                -    R¹⁶ represents H or (C₁-C₃)alkyl, or

        -   R¹⁰ and R¹¹ may be joined to form a saturated 5-6-membered            N-containing ring which is optionally substituted up to two            times by            -   OH,            -   NR¹⁷R¹⁸, wherein                -   R¹⁷ and R¹⁸ are H or (C₁-C₃)alkyl, or by            -   (C₁-C₃)alkyl which is optionally substituted up to two                times by halogen, OH, or O(C₁-C₃)alkyl;

    -   G12) OSO₂NR²³R²⁴ wherein        -   R²³ and R²⁴ independently represent H, CH₃, or (C₂-C₄)alkyl            which may optionally be substituted once by OH or NR²⁵R²⁶,            wherein            -   R²⁵ and R²⁶ independently represent H or (C₁-C₃)alkyl;

    -   G13) CN;

    -   G22)

-   -    wherein        -   Q″ is O or NR³⁰, and        -   R³⁰ is            -   H,            -   cyclopropyl, or            -   (C₁-C₃)alkyl which is optionally substituted once by                halogen, OH, or O(C₁-C₃)alkyl;    -   G29) NR⁴¹SO₂NR⁴²R⁴³ wherein        -   R⁴¹ represents H, or (C₁-C₄)alkyl, and        -   R⁴² and R⁴³ independently represent H, CH₃, or (C₂-C₃)alkyl            which may optionally be substituted once by —OH or NR⁴⁴R⁴⁵,            wherein            -   R⁴⁴ and R⁴⁵ independently represent H or (C₁-C₃)alkyl;                and    -   G31) N(R⁴⁸)C(O)R⁴⁹ wherein        -   R⁴⁸ represents H or (C₁-C₃)alkyl; and        -   R⁴⁹ represents            -   (CH₂)₁₋₃—CO₂H,            -   O(C₂-C₄)alkyl,            -   (CH₂)₁₋₄—NR⁵⁰R⁵¹ wherein                -   R⁵⁰ and R⁵¹ independently represent H or                    (C₁-C₃)alkyl, or            -   CH(R⁵²)—NR⁵³R⁵⁴ wherein                -   R⁵² represents (CH₂)₁₋₄—NH₂, CH₂OH, CH(CH₃)OH, or                    (C₁-C₃)alkyl; and                -   R⁵³ and R⁵⁴ independently represent H or                    (C₁-C₃)alkyl.

In a third embodiment the invention relates to a compound of the abovesecond embodiment, having the structure

-   wherein the definitions of the variables are as given above in the    second embodiment, except that in this third embodiment-   R¹ represents H;-   R² represents O(C₁-C₃)alkyl or NR³R⁴    -   wherein R³ and R⁴ are H or (C₁-C₃)alkyl;-   R^(2a) represents H;-   L represents O or CR⁶R⁷ wherein    -   R⁶ and R⁷ are independently H, CH₃, or OH;-   G″ represents a substituent selected from the group consisting of    O(C₁-C₃)alkyl, halogen, and CF₃;-   n and n′ are independently 0 or 1, and provisos 1-3 do not apply;-   G and G′ moieties are independently selected from the group    consisting of:    -   G1) Cl or F;    -   G2) O(C₁-C₃)alkyl;    -   G3) OH;    -   G4) (C₁-C₃)alkyl, which is optionally substituted up to three        times by halogen;    -   G5) OCF₃;    -   G8) NR¹⁰R¹¹, wherein        -   R¹⁰ and R¹¹ are independently selected from            -   H,            -   CH₃,            -   cyclopropyl,            -   benzyl,            -   NR¹²R¹³ wherein                -   R¹² and R¹³ are independently H or (C₁-C₃)alkyl,                    provided that both R¹⁰ and R¹¹ are not NR¹²R¹³                    simultaneously, and            -   (C₂-C₄)alkyl which is optionally substituted up to three                times by halogen, and up to two times by substituent                groups independently selected from hydroxyl,                O(C₁-C₃)alkyl, and NR¹⁴R¹⁵, wherein                -   R¹⁴ and R¹⁵ are independently H or (C₁-C₃)alkyl, or                -   R¹⁴ and R¹⁵ can join to form a heterocycle of                    formula

-   -   -   -   -    wherein                -    Q represents CH₂, O, or NR¹⁶, and                -    R¹⁶ represents H or (C₁-C₃)alkyl,

    -   G12) OSO₂NR²³R²⁴ wherein        -   R²³ and R²⁴ independently represent H, CH₃, or (C₂-C₄)alkyl            which may optionally be substituted once by OH or NR²⁵R²⁶,            wherein            -   R²⁵ and R²⁶ independently represent H or (C₁-C₃)alkyl;

    -   G13) CN;

    -   G22)

-   -    wherein        -   Q″ is O or NR³⁰, and        -   R³⁰ is H or (C₁-C₃)alkyl; and    -   G31) N(R⁴⁸)C(O)R⁴⁹ wherein        -   R⁴⁸ represents H or (C₁-C₃)alkyl; and        -   R⁴⁹ represents            -   (CH₂)₁₋₃—CO₂H,            -   O(C₂-C₄)alkyl,            -   (CH₂)₁₋₄—NR⁵⁰R⁵¹ wherein                -   R⁵⁰ and R⁵¹ independently represent H or                    (C₁-C₃)alkyl, or            -   CH(R⁵²)—NR⁵³R⁵⁴ wherein                -   R⁵² represents (CH₂)₁₋₄—NH₂, CH₂OH, CH(CH₃)OH, or                    (C₁-C₃)alkyl; and                -   R⁵³ and R⁵⁴ independently represent H or                    (C₁-C₃)alkyl.

In a fourth embodiment, the invention relates to a compound of the abovefirst embodiment, having the structure

-   wherein the definitions of the variables are as given above in the    first embodiment, except that in this fourth embodiment-   R¹ represents H;-   M represents CH;-   J represents a heteroaromatic ring selected from the group    consisting of

-   Y represents an aromatic or heteroaromatic ring selected from the    group consisting of

-   n and n′ are independently 0, 1, 2, or 3, subject to the provisos    that    -   1) ring J and ring Y each may be substituted independently up to        3 times by substituents listed below as numbers G1-G2, to a        maximum total of 4 substituents on rings J and Y,    -   2) ring J and ring Y each may be substituted independently up to        2 times by substituents listed below as numbers G3-G5 and G8, to        a maximum total of 3 substituents on rings J and Y, and    -   3) ring J and ring Y each may be substituted independently once        by a substituent selected from those listed below as numbers        G12, G21, G25, G26, and G31;-   and subject to the further proviso    -   4) when J is pyridyl, n is 1, 2, or 3;-   and proviso 5 does not apply;-   G and G′ moieties are independently selected from the group    consisting of:    -   G1) halogen;    -   G2) O(C₁-C₄)alkyl which optionally is substituted up to two        times by O(C₁-C₂)alkyl;

G3) OH;

-   -   G4) (C₁-C₅)alkyl, which is optionally substituted independently        up to two times by groups selected from hydroxyl and cyano, or        up to three times by halogen;    -   G5) OCF₃;    -   G8) NR¹⁰R¹¹, wherein        -   R¹⁰ and R¹¹ are independently selected from            -   H,            -   CH₃,            -   cyclopropyl,            -   benzyl,            -   NR¹²R¹³ wherein                -   R¹² and R¹³ are independently H or (C₁-C₃)alkyl,                    provided that both R¹⁰ and R¹¹ are not NR¹²R¹³                    simultaneously, and            -   (C₂-C₄)alkyl which is optionally substituted up to three                times by halogen, and up to two times by substituent                groups independently selected from hydroxyl,                O(C₁-C₃)alkyl, and NR¹⁴R¹⁵, wherein                -   R¹⁴ and R¹⁵ are independently H or (C₁-C₃)alkyl, or                -   R¹⁴ and R¹⁵ can join to form a heterocycle of                    formula

-   -   -   -   -    wherein                -    Q represents CH₂, O, or NR¹⁶, and                -    R¹⁶ represents H or (C₁-C₃)alkyl, or

        -   R¹⁰ and R¹¹ may be joined to form a saturated 5-6-membered            N-containing ring which is optionally substituted up to two            times by            -   OH,            -   NR¹⁷R¹⁸, wherein                -   R¹⁷ and R¹⁸ are H or (C₁-C₃)alkyl, or by            -   (C₁-C₃)alkyl which is optionally substituted up to two                times by halogen, OH, or O(C₁-C₃)alkyl;

    -   G12) OSO₂NR²³R²⁴ wherein        -   R²³ and R²⁴ independently represent H, CH₃, or (C₂-C₄)alkyl            which may optionally be substituted once by OH or NR²⁵R²⁶,            wherein            -   R²⁵ and R²⁶ independently represent H or (C₁-C₃)alkyl;

    -   G21) C(O)NR²⁸R²⁹, wherein        -   R²⁸ and R²⁹ are independently selected from            -   H,            -   cyclopropyl, provided that both R²⁸ and R²⁹ are not                simultaneously cyclopropyl,

-   -   -   -    provided that this group does not constitute both                -   R²⁸ and R²⁹ simultaneously, and            -   (C₁-C₃)alkyl which is optionally substituted up to two                times by OH; or            -   R²⁸ and R²⁹ may be joined to form a saturated                5-6-membered N-containing ring which is optionally                substituted up to two times by OH, or by (C₁-C₃)alkyl                which in turn is optionally substituted up to two times                by OH or O(C₁-C₃)alkyl;

    -   G25)

-   -    wherein        -   Q^(iv) is O or NR³⁴; and        -   R³⁴ is H, (C₁-C₃)alkyl, or cyclopropyl;    -   G26) C(O)NR³⁵(CH₂)_(f)OR³⁶ wherein        -   R³⁵ is H, (C₁-C₃)alkyl, or cyclopropyl;        -   R³⁶ is (C₁-C₆)alkyl optionally substituted up to two times            by halogen, OH, or O(C₁-C₃)alkyl, and        -   the subscript “f” is an integer of 2-4; and    -   G31) N(R⁴⁸)C(O)R⁴⁹ wherein        -   R⁴⁸ represents H or (C₁-C₃)alkyl; and        -   R⁴⁹ represents            -   (CH₂)₁₋₃—CO₂H,            -   O(C₂-C₄)alkyl,            -   (CH₂)₁₋₄—NR⁵⁰R⁵¹ wherein                -   R⁵⁰ and R⁵¹ independently represent H or                    (C₁-C₃)alkyl, or            -   CH(R⁵²)—NR⁵³R⁵⁴ wherein                -   R⁵² represents (CH₂)₁₋₄—NH₂, CH₂OH, CH(CH₃)OH, or                    (C₁-C₃)alkyl; and                -   R⁵³ and R⁵⁴ independently represent H or                    (C₁-C₃)alkyl.

In a fifth embodiment, the invention relates to a compound of the abovefourth embodiment, having the structure

-   wherein the definitions of the variables are as given above in the    fourth embodiment, except that in this fifth embodiment-   R¹ represents H;-   R² represents O(C₁-C₃)alkyl or NR³R⁴    -   wherein R³ and R⁴ are H or (C₁-C₃)alkyl;-   R^(2a) represents H;-   L represents O or CR⁶R⁷, wherein    -   R⁶ and R⁷ are independently H, CH₃, or OH;-   G″ represents a substituent selected from the group consisting of    O(C₁-C₃)alkyl, halogen, and CF₃;-   n and n′ are independently 0 or 1, and provisos 1-3 do not apply;-   G and G′ moieties are independently selected from the group    consisting of:    -   G1) Cl or F;    -   G2) O(C₁-C₃)alkyl;    -   G3) OH;    -   G4) (C₁-C₃)alkyl, which is optionally substituted up to three        times by halogen;    -   G5) OCF₃;    -   G8) NR¹⁰R¹¹, wherein        -   R¹⁰ and R¹¹ are independently selected from            -   H,            -   CH₃,            -   cyclopropyl,            -   benzyl,            -   NR¹²R¹³ wherein                -   R¹² and R¹³ are independently H or (C₁-C₃)alkyl,                    provided that both R¹⁰ and R¹¹ are not NR¹²R¹³                    simultaneously, and            -   (C₂-C₄)alkyl which is optionally substituted up to three                times by halogen, and up to two times by substituent                groups independently selected from hydroxyl,                O(C₁-C₃)alkyl, and NR¹⁴R¹⁵, wherein                -   R¹⁴ and R¹⁵ are independently H or (C₁-C₃)alkyl, or                -   R¹⁴ and R¹⁵ can join to form a heterocycle of                    formula

-   -   -   -   -    wherein                -    Q represents CH₂, O, or NR¹⁶, and                -    R¹⁶ represents H or (C₁-C₃)alkyl,

    -   G12) OSO₂NR²³R²⁴ wherein        -   R²³ and R²⁴ independently represent H, CH₃, or (C₂-C₄)alkyl            which may optionally be substituted once by OH or NR²⁵R²⁶,            wherein            -   R²⁵ and R²⁶ independently represent H or (C₁-C₃)alkyl;

    -   G21) C(O)NR²⁸R²⁹, wherein        -   R²⁸ and R²⁹ are independently selected from            -   H and            -   (C₁-C₃)alkyl which is optionally substituted up to two                times by OH;

    -   G25)

-   -    wherein        -   Q^(iv) is O or NR³⁴; and        -   R³⁴ is H or (C₁-C₃)alkyl;    -   G26) C(O)NR³⁵(CH₂)_(f)OR³⁶ wherein        -   R³⁵ is H or (C₁-C₃)alkyl;        -   R³⁶ is (C₁-C₆)alkyl optionally substituted up to two times            by halogen, OH, or O(C₁-C₃)alkyl, and        -   the subscript “f” is an integer of 2-4; and    -   G31) N(R⁴⁸)C(O)R⁴⁹ wherein        -   R⁴⁸ represents H or (C₁-C₃)alkyl; and        -   R⁴⁹ represents            -   (CH₂)₁₋₃—CO₂H,            -   O(C₂-C₄)alkyl,            -   (CH₂)₁₋₄—NR⁵⁰R⁵¹ wherein                -   R⁵⁰ and R⁵¹ independently represent H or                    (C₁-C₃)alkyl, or            -   CH(R⁵²)—NR⁵³R⁵⁴ wherein                -   R⁵² represents (CH₂)₁₋₄—NH₂, CH₂OH, CH(CH₃)OH, or                    (C₁-C₃)alkyl; and                -   R⁵³ and R⁵⁴ independently represent H or                    (C₁-C₃)alkyl.

In a sixth embodiment, the invention relates to a compound of the abovefirst embodiment, having the structure

-   wherein the definitions of the variables are as given above in the    first embodiment, except that in this sixth embodiment-   R¹ represents H;-   M represents CH;-   J represents an aromatic or heteroaromatic ring selected from the    group consisting of

-   Y represents an aromatic or heteroaromatic ring selected from the    group consisting of

-   n and n′ are independently 0, 1, 2, or 3, subject to the provisos    that    -   1) ring J and ring Y each may be substituted independently up to        3 times by substituents listed below as numbers G1-G2, to a        maximum total of 4 substituents on rings J and Y,    -   2) ring J and ring Y each may be substituted independently up to        2 times by substituents listed below as numbers G3-G5 and G8, to        a maximum total of 3 substituents on rings J and Y, and    -   3) ring J and ring Y each may be substituted independently once        by a substituent selected from those listed below as numbers        G12, G22, and G31;-   and subject to the further proviso    -   4) when J is pyridyl, n is 1, 2, or 3;-   and proviso 5 does not apply;-   G and G′ moieties are independently selected from the group    consisting of:    -   G1) halogen;    -   G2) O(C₁-C₄)alkyl which optionally is substituted up to two        times by O(C₁-C₂)alkyl;    -   G3) OH;    -   G4) (C₁-C₅)alkyl, which is optionally substituted independently        up to two times by groups selected from hydroxyl and cyano, or        up to three times by halogen;    -   G5) OCF₃;    -   G8) NR¹⁰R¹¹, wherein        -   R¹⁰ and R¹¹ are independently selected from            -   H,            -   CH₃,            -   cyclopropyl,            -   benzyl,            -   NR¹²R¹³ wherein                -   R¹² and R¹³ are independently H or (C₁-C₃)alkyl,                    provided that both R¹⁰ and R¹¹ are not NR¹²R¹³                    simultaneously, and            -   (C₂-C₄)alkyl which is optionally substituted up to three                times by halogen, and up to two times by substituent                groups independently selected from hydroxyl,                O(C₁-C₃)alkyl, and NR¹⁴R¹⁵, wherein                -   R¹⁴ and R¹⁵ are independently H or (C₁-C₃)alkyl, or                -   R¹⁴ and R¹⁵ can join to form a heterocycle of                    formula

-   -   -   -   -    wherein                -    Q represents CH₂, O, or NR¹⁶, and                -    R¹⁶ represents H or (C₁-C₃)alkyl, or

        -   R¹⁰ and R¹¹ may be joined to form a saturated 5-6-membered            N-containing ring which is optionally substituted up to two            times by            -   OH,            -   NR¹⁷R¹⁸, wherein                -   R¹⁷ and R¹⁸ are H or (C₁-C₃)alkyl, or by            -   (C₁-C₃)alkyl which is optionally substituted up to two                times by halogen, OH, or O(C₁-C₃)alkyl;

    -   G12) OSO₂NR²³R²⁴ wherein        -   R²³ and R²⁴ independently represent H, CH₃, or (C₂-C₄)alkyl            which may optionally be substituted once by OH or NR²⁵R²⁶,            wherein            -   R²⁵ and R²⁶ independently represent H or (C₁-C₃)alkyl;

    -   G22)

-   -    wherein        -   Q″ is O or NR³⁰, and        -   R³⁰ is            -   H,            -   cyclopropyl, or            -   (C₁-C₃)alkyl which is optionally substituted once by                halogen, OH, or O(C₁-C₃)alkyl; and    -   G31) N(R⁴⁸)C(O)R⁴⁹ wherein        -   R⁴⁸ represents H or (C₁-C₃)alkyl; and        -   R⁴⁹ represents            -   (CH₂)₁₋₃—CO₂H,            -   O(C₂-C₄)alkyl,            -   (CH₂)₁₋₄—NR⁵⁰R⁵¹ wherein                -   R⁵⁰ and R⁵¹ independently represent H or                    (C₁-C₃)alkyl, or            -   CH(R⁵²)—NR⁵³R⁵⁴ wherein                -   R⁵² represents (CH₂)₁₋₄—NH₂, CH₂OH, CH(CH₃)OH, or                    (C₁-C₃)alkyl; and                -   R⁵³ and R⁵⁴ independently represent H or                    (C₁-C₃)alkyl.

In a seventh embodiment, the invention relates to a compound of theabove sixth embodiment, having the structure

-   wherein the definitions of the variables are as given above in the    sixth embodiment, except that in this seventh embodiment-   R¹ represents H;-   R² represents O(C₁-C₃)alkyl, or NR³R⁴    -   wherein R³ and R⁴ are H or (C₁-C₃)alkyl;-   R^(2a) represents H;-   L represents O or CR⁶R⁷, wherein    -   R⁶ and R⁷ are independently H, CH₃, or OH;-   G″ represents a substituent selected from the group consisting of    O(C₁-C₃)alkyl, halogen, and CF₃;-   n and n′ are independently 0 or 1, and provisos 1-3 do not apply;-   G and G′ moieties are independently selected from the group    consisting of:    -   G1) Cl or F;    -   G2) O(C₁-C₃)alkyl;    -   G3) OH;    -   G4) (C₁-C₃)alkyl, which is optionally substituted up to three        times by halogen;    -   G5) OCF₃;    -   G8) NR¹⁰R¹¹, wherein        -   R¹⁰ and R¹¹ are independently selected from            -   H,            -   CH₃,            -   cyclopropyl,            -   benzyl,            -   NR¹²R¹³ wherein                -   R¹² and R¹³ are independently H or (C₁-C₃)alkyl,                    provided that both R¹⁰ and R¹¹ are not NR¹²R¹³                    simultaneously, and            -   (C₂-C₄)alkyl which is optionally substituted up to three                times by halogen, and up to two times by substituent                groups independently selected from hydroxyl,                O(C₁-C₃)alkyl, and NR¹⁴R¹⁵, wherein                -   R¹⁴ and R¹⁵ are independently H or (C₁-C₃)alkyl, or                -   R¹⁴ and R¹⁵ can join to form a heterocycle of                    formula

-   -   -   -   -    wherein                -    Q represents CH₂, O, or NR¹⁶, and                -    R¹⁶ represents H or (C₁-C₃)alkyl;

    -   G12) OSO₂NR²³R²⁴ wherein        -   R²³ and R²⁴ independently represent H, CH₃, or (C₂-C₄)alkyl            which may optionally be substituted once by OH or NR²⁵R²⁶            wherein            -   R²⁵ and R²⁶ independently represent H or (C₁-C₃)alkyl;

    -   G22)

-   -    wherein        -   Q″ is O or NR³⁰, and        -   R³⁰ is H or (C₁-C₃)alkyl; and    -   G31) N(R⁴⁸)C(O)R⁴⁹ wherein        -   R⁴⁸ represents H or (C₁-C₃)alkyl; and        -   R⁴⁹ represents            -   (CH₂)₁₋₃—CO₂H,            -   O(C₂-C₄)alkyl,            -   (CH₂)₁₋₄—NR⁵⁰R⁵¹ wherein                -   R⁵⁰ and R⁵¹ independently represent H or                    (C₁-C₃)alkyl, or            -   CH(R⁵²)—NR⁵³R⁵⁴ wherein                -   R⁵² represents (CH₂)₁₋₄—NH₂, CH₂OH, CH(CH₃)OH, or                    (C₁-C₃)alkyl; and                -   R⁵³ and R⁵⁴ independently represent H or                    (C₁-C₃)alkyl.

In an eighth embodiment, the invention relates to a compound of thestructure

-   -   wherein    -   R¹ represents H;    -   R² represents NH₂;    -   L represents O;    -   M is CH    -   n is 1;    -   n′ is 0, 1, or 2;    -   G is a moiety selected from the group consisting of methyl and        trifluoromethyl;    -   G′ is a moiety selected from the group consisting of methyl and        amino;    -   J is pyridyl or pyrimidyl;    -   Y is phenyl, pyridyl or pyrimidyl;    -   or a pharmaceutically acceptable salt thereof.

Pharmaceutically acceptable salts of these compounds as well as commonlyused prodrugs of these compounds such as, for example, O-acylderivatives of invention compounds which contain hydroxy groups, esterderivatives of invention compounds which contain carboxyl groups, andamide derivatives of invention compounds which contain amino groups, arealso within the scope of the invention.

It is to be understood that:

1) in compounds of the invention in which an alkyl moiety may bearsubstituents such as amino, hydroxyl, alkoxy, and halogen groups, asingle carbon atom of this alkyl moiety may not simultaneously bear twogroups independently selected from amino, hydroxyl, and alkoxy; andwhere this alkyl moiety bears a halogen, it may not simultaneously alsobear an amino, hydroxyl, or alkoxy substituent.

2) in compounds of the invention in which any moiety is defined in termsof a numerical range of atoms and this moiety is further permitted tobear up to a certain number of substituents, if the total number ofsubstituents possible exceeds the number of valences available formoieties at the lower end of the defined numerical range of atoms, thenthe number of substituents is limited to the number of availablevalences. For example, if a (C₁-C₃)alkyl moiety if defined as optionallybearing up to three halogens and up to two other defined substituents,this means that a C₁-alkyl group could bear up to three substituents(the number of available valences), all of which could be halogen, butno more than two of which could be other defined substituent groups.

The compounds of Formula (I) may contain one or more asymmetric centers,depending upon the location and nature of the various substituentsdesired. Asymmetric carbon atoms may be present in the (R) or (S)configuration. Preferred isomers are those with the absoluteconfiguration which produces the compound of Formula (I) with the moredesirable biological activity. In certain instances, asymmetry may alsobe present due to restricted rotation about a given bond, for example,the central bond adjoining two aromatic rings of the specifiedcompounds.

It is intended that all isomers (including enantiomers anddiastereomers), either by nature of asymmetric centers or by restrictedrotation as described above, as separated, pure or partially purifiedisomers or racemic mixtures thereof, be included within the scope of theinstant invention. The purification of said isomers and the separationof said isomeric mixtures may be accomplished by standard techniquesknown in the art.

The terms identified above have the following meaning throughout:

The term “optionally substituted” means that the moiety so modified mayhave from none to up to at least the highest number of substituentsindicated. The substituent may replace any H atom on the moiety somodified as long as the replacement is chemically possible andchemically stable. When there are two or more substituents on anymoiety, each substituent is chosen independently of any othersubstituent and can, accordingly, be the same or different.

The term “halogen” means an atom selected from Cl, Br, F, and I.

The terms “(C₁-C₂)alkyl,” “(C₁-C₃)alkyl” “(C₁-C₄)alkyl” “(C₁-C₅)alkyl,”and “(C₁-C₆)alkyl” mean linear or branched saturated carbon groupshaving from about 1 to about 2, about 3, about 4, about 5 or about 6 Catoms, respectively. Such groups include, but are not limited to,methyl, ethyl, n-propyl, isopropyl, sec-butyl, n-hexyl, and the like.

The term “alkylenyl” means a divalent linear or branched saturatedcarbon chain, usually having from about 1 to about 3 carbon atoms inthis application. Such chains include, but are not limited to methylene(—CH₂—), ethylenyl (—CH₂CH₂)—, and propylenyl (—CH₂CH₂CH₂—) and thelike.

The term “(C₃-C₆)cycloalkyl” means a saturated monocyclic alkyl group offrom about 3 to about 6 carbon atoms and includes such groups ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

Pharmaceutical Compositions

The invention also relates to pharmaceutical compositions comprising atleast one of the compounds of the invention, or a salt or prodrugthereof, in a pharmaceutically acceptable carrier.

Method of Treating Hyperproliferative Disorders

The present invention also relates to a method of using the compoundsdescribed above, including salts, prodrugs, and correspondingpharmaceutical compositions thereof, to treat mammalianhyperproliferative disorders. This method comprises administering to apatient an amount of a compound of this invention, or a pharmaceuticallyacceptable salt or prodrug thereof, which is effective to treat thepatient's hyperproliferative disorder. A patient, for the purpose ofthis invention, is a mammal, including a human, in need of treatment fora particular hyperproliferative disorder. A pharmaceutically effectiveamount of a compound or composition is that amount which produces adesired result or exerts an influence on the particularhyperproliferative disorder being treated.

Hyperproliferative disorders include but are not limited to solidtumors, such as cancers of the breast, respiratory tract, brain,reproductive organs, digestive tract, urinary tract, eye, liver, skin,head and neck, thyroid, parathyroid and their distant metastases. Thesedisorders also include lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumor.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumors of the female reproductive organsinclude, but are not limited to endometrial, cervical, ovarian, vaginal,and vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, and urethral cancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited tolaryngeal/hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and lipand oral cavity cancer.

Lymphomas include, but are not limited to AIDS-related lymphoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease,and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The utility of the compounds of the present invention can beillustrated, for example, by their activity in vitro in the in vitrotumor cell proliferation assay described below. The link betweenactivity in tumor cell proliferation assays in vitro and anti-tumoractivity in the clinical setting has been well established in the art.For example, the therapeutic utility of taxol (Silvestrini et al. StemCells 1993, 11(6), 528-35), taxotere (Bissery et al. Anti Cancer Drugs1995, 6(3), 339), and topoisomerase inhibitors (Edelman et al. CancerChemother. Pharmacol. 1996, 37(5), 385-93) was demonstrated with the useof in vitro tumor proliferation assays.

In this application, where the plural form is used for compounds, salts,and the like, this is taken to mean also a single compound, salt, or thelike.

Salts are especially the pharmaceutically acceptable salts of compoundsof formula I such as, for example, acid addition salts, preferably withorganic or inorganic acids, from compounds of formula I with a basicnitrogen atom. Suitable inorganic acids are, for example, halogen acidssuch as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitableorganic acids are, for example, carboxylic, phosphonic, sulfonic, orsulfamic acids, for example acetic acid, propionic acid, octanoic acid,decanoic acid, dodecanoic acid, glycolic acid, lactic acid,-hydroxybutyric acid, gluconic acid, glucosemonocarboxylic acid, fumaricacid, succinic acid, adipic acid, pimelic acid, suberic acid, azeiaicacid, malic acid, tartaric acid, citric acid, glucaric acid, galactaricacid, amino acids, such as glutamic acid, aspartic acid,N-methylglycine, acetylaminoacetic acid, N-acetylasparagine orN-acetylcysteine, pyruvic acid, acetoacetic acid, phosphoserine, 2- or3-glycerophosphoric acid.

The compounds of the invention may be administered orally, dermally,parenterally, by injection, by inhalation or spray, or sublingually,rectally or vaginally in dosage unit formulations. The term‘administered by injection’ includes intravenous, intraarticular,intramuscular, subcutaneous and parenteral injections, as well as use ofinfusion techniques. Dermal administration may include topicalapplication or transdermal administration. One or more compounds may bepresent in association with one or more non-toxic pharmaceuticallyacceptable carriers and if desired, other active ingredients.

Compositions intended for oral use may be prepared according to anysuitable method known to the art for the manufacture of pharmaceuticalcompositions. Such compositions may contain one or more agents selectedfrom the group consisting of diluents, sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepalatable preparations.

Tablets contain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; and binding agents, forexample magnesium stearate, stearic acid or talc. The tablets may beuncoated or they may be coated by known techniques to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate maybe employed. These compounds may also be prepared in solid, rapidlyreleased form.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions containing the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions may alsobe used. Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolsuch as polyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives, for exampleethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, flavoring and coloringagents, may also be present.

The compounds may also be in the form of non-aqueous liquidformulations, e.g., oily suspensions which may be formulated bysuspending the active ingredients in a vegetable oil, for examplearachis oil, olive oil, sesame oil or peanut oil, or in a mineral oilsuch as liquid paraffin. The oily suspensions may contain a thickeningagent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteningagents such as those set forth above, and flavoring agents may be addedto provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oil phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The compounds may also be administered in the form of suppositories forrectal or vaginal administration of the drug. These compositions can beprepared by mixing the drug with a suitable non-irritating excipientwhich is solid at ordinary temperatures but liquid at the rectal orvaginal temperature and will therefore melt in the rectum or vagina torelease the drug. Such materials include cocoa butter and polyethyleneglycols.

Compounds of the invention may also be administered transdermally usingmethods known to those skilled in the art (see, for example: Chien;“Transdermal Controlled Systemic Medications”; Marcel Dekker, Inc.;1987. Lipp et al. WO 94/04157 3 Mar. 94). For example, a solution orsuspension of a compound of Formula I in a suitable volatile solventoptionally containing penetration enhancing agents can be combined withadditional additives known to those skilled in the art, such as matrixmaterials and bacteriocides. After sterilization, the resulting mixturecan be formulated following known procedures into dosage forms. Inaddition, on treatment with emulsifying agents and water, a solution orsuspension of a compound of Formula I may be formulated into a lotion orsalve.

Suitable solvents for processing transdermal delivery systems are knownto those skilled in the art, and include lower alcohols such as ethanolor isopropyl alcohol, lower ketones such as acetone, lower carboxylicacid esters such as ethyl acetate, polar ethers such as tetrahydrofuran,lower hydrocarbons such as hexane, cyclohexane or benzene, orhalogenated hydrocarbons such as dichloromethane, chloroform,trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solventsmay also include mixtures one or more materials selected from loweralcohols, lower ketones, lower carboxylic acid esters, polar ethers,lower hydrocarbons, halogenated hydrocarbons.

Suitable penetration enhancing materials for transdermal deliverysystems are known to those skilled in the art, and include, for example,monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol orbenzyl alcohol, saturated or unsaturated C₈-C₁₈ fatty alcohols such aslauryl alcohol or cetyl alcohol, saturated or unsaturated C₈-C₁₈ fattyacids such as stearic acid, saturated or unsaturated fatty esters withup to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl isobutyl tert-butyl or monoglycerin esters of acetic acid,capronic acid, lauric acid, myristinic acid, stearic acid, or palmiticacid, or diesters of saturated or unsaturated dicarboxylic acids with atotal of up to 24 carbons such as diisopropyl adipate, diisobutyladipate, diisopropyl sebacate, diisopropyl maleate, or diisopropylfumarate. Additional penetration enhancing materials includephosphatidyl derivatives such as lecithin or cephalin, terpenes, amides,ketones, ureas and their derivatives, and ethers such as dimethylisosorbid and diethyleneglycol monoethyl ether. Suitable penetrationenhancing formulations may also include mixtures one or more materialsselected from monohydroxy or polyhydroxy alcohols, saturated orunsaturated C₈-C₁₈ fatty alcohols, saturated or unsaturated C₈-C₁₈ fattyacids, saturated or unsaturated fatty esters with up to 24 carbons,diesters of saturated or unsaturated dicarboxylic acids with a total ofup to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones,ureas and their derivatives, and ethers.

Suitable binding materials for transdermal delivery systems are known tothose skilled in the art and include polyacrylates, silicones,polyurethanes, block polymers, styrene-butadiene copolymers, and naturaland synthetic rubbers. Cellulose ethers, derivatized polyethylenes, andsilicates may also be used as matrix components. Additional additives,such as viscous resins or oils may be added to increase the viscosity ofthe matrix.

For all regimens of use disclosed herein for compounds of Formula I, thedaily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg oftotal body weight. The daily dosage for administration by injection,including intravenous, intramuscular, subcutaneous and parenteralinjections, and use of infusion techniques will preferably be from 0.01to 200 mg/Kg of total body weight. The daily rectal dosage regimen willpreferably be from 0.01 to 200 mg/Kg of total body weight. The dailyvaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg oftotal body weight. The daily topical dosage regimen will preferably befrom 0.1 to 200 mg administered between one to four times daily. Thetransdermal concentration will preferably be that required to maintain adaily dose of from 0.01 to 200 mg/Kg. The daily inhalation dosageregimen will preferably be from 0.01 to 10 mg/Kg of total body weight.

It will be appreciated by those skilled in the art that the particularmethod of administration will depend on a variety of factors, all ofwhich are considered routinely when administering therapeutics. It willalso be understood, however, that the specific dose level for any givenpatient will depend upon a variety of factors, including, but notlimited to the activity of the specific compound employed, the age ofthe patient, the body weight of the patient, the general health of thepatient, the gender of the patient, the diet of the patient, time ofadministration, route of administration, rate of excretion, drugcombinations, and the severity of the condition undergoing therapy. Itwill be further appreciated by one skilled in the art that the optimalcourse of treatment, i.e., the mode of treatment and the daily number ofdoses of a compound of Formula I or a pharmaceutically acceptable saltthereof given for a defined number of days, can be ascertained by thoseskilled in the art using conventional treatment tests.

The compounds according to the invention can be converted intopharmaceutical preparations as follows:

Tablet:

Composition:

100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50mg of maize starch (native), 10 mg of polyvinylpyrrolidone (PVP 25)(from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg, diameter 8 mm, curvature radius 12 mm.

Preparation:

The mixture of active component, lactose and starch is granulated with a5% solution (m/m) of the PVP in water. After drying, the granules aremixed with magnesium stearate for 5 min. This mixture is molded using acustomary tablet press (tablet format, see above). The molding forceapplied is typically 15 kN.

Suspension for Oral Administration:

Composition:

1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mgof Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.

A single dose of 100 mg of the compound according to the invention isprovided by 10 ml of oral suspension.

Preparation:

The Rhodigel is suspended in ethanol and the active component is addedto the suspension. The water is added with stirring. Stirring iscontinued for about 6 h until the swelling of the Rhodigel is complete.

Solution for Intravenous Administration:

Composition:

1 mg of the compound of Example 1, 15 g of polyethylene glycol 400 and250 g of water for injection.

Preparation:

The compound of Example 1 is dissolved with polyethylene glycol 400 inthe water with stirring. The solution is sterilized by filtration (porediameter 0.22 μm) and dispensed under aseptic conditions intoheat-sterilized infusion bottles. These are closed with infusionstoppers and crimped caps.

General Preparative Methods

The compounds of the invention have the general chemical structure shownbelow and may be prepared by the use of known chemical reactions andprocedures. The particular process to be utilized in the preparation ofthe compounds of this invention depends upon the specific compounddesired. Such factors as the selection of the specific J and Y moieties,as well as the specific substituents possible at various locations onthe molecule, all play a role in the path to be followed in thepreparation of the specific compounds of this invention. Those factorsare readily recognized by one skilled in the art.

Nevertheless, the following general preparative methods are presented toaid the reader in synthesizing the compounds of the invention, with moredetailed particular examples being presented below in the experimentalsection describing the working examples.

All variable groups of these methods are as described in the genericdescription if they are not specifically defined below. When a variablegroup or substituent with a given symbol (i.e. G, G′, M) is used morethan once in a given structure, it is to be understood that each ofthese groups or substituents may be independently varied within therange of definitions for that symbol.

Within these general methods the variable Z is equivalent to the moiety

in which each variable group or substituent is allowed to varyindependently within the limits defined for that symbol.

Within these general methods the variable E is equivalent to the moiety

in which each variable group or substituent is allowed to varyindependently within the limits defined for that symbol.

It is recognized that compounds of the invention with each claimedoptional functional group cannot be prepared with each of thebelow-listed methods. Within the scope of each method optionalsubstituents are used which are stable to the reaction conditions, orthe functional groups which may participate in the reactions are presentin protected form where necessary, and the removal of such protectivegroups is completed at appropriate stages by methods well known to thoseskilled in the art.

Additional compounds of formula (I) may be prepared from other formula(I) compounds by elaboration of functional groups present. Suchelaboration includes, but is not limited to, hydrolysis, reduction,oxidation, alkylation, acylation, esterification, amidation anddehydration reactions. Such transformations may in some instancesrequire the use of protecting groups by the methods disclosed in T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis; Wiley:New York, (1999), and incorporated herein by reference. Such methodswould be initiated after synthesis of the desired compound or at anotherplace in the synthetic route that would be readily apparent to oneskilled in the art.

General Method A—Invention compounds of formula 5 in which Z and E areas defined above, may be conveniently prepared according to a reactionsequence as shown in General Method “A”. Thus, amidine or guanidine 1and β-ketoester 2 are either obtained from commercial sources or made byone skilled in the art according to published procedures (amidine 1:Granik et al Russ Chem. Rev. 1983, 52, 377-393; β-ketoester 2: Tabuchi,H. et al. Synlett 1993, (9), 651-2). Amidine or guanidine 1 is treatedwith β-ketoester 2 in a refluxing mixed solvent such as alcohol andtoluene or benzene to furnish pyrimidinone intermediate 3. The alcoholis typically a lower molecular weight alcohol such as ethanol,isopropanol, n-propanol, n-butanol, iso-butanol, or t-butanol. Compound3 is treated with a chlorinating agent such as phosphorous oxychloride,thionyl chloride or phosphorous pentachloride to yield chloropyrimidineintermediate 4. Intermediate 4 is reacted with a nucleophile of formulaNHR¹Z in a refluxing solvent such as alcohol, water, DMF, DMA,acetonitrile, acetone, dioxane or DMSO to furnish the invention compoundof formula 5 [formula (I), where R^(2a) is H]. Such reactions can alsobe done in a melt free of solvent or in a solvent catalyzed by acidssuch as HCl, H₂SO₄ or bases such as but not limited to triethylamine,Cs₂CO₃, K₂CO₃, Na₂CO₃, K₃PO₄, Na₃PO₄, NaOH, KOH, NaH, NaNH₂, KNH₂, or asodium or potassium alkoxide or 1,8-diazobicyclo[5.4.0]undec-7-ene(DBU). Invention compounds of formula 5a [(I) where R^(2a) is Cl, Br orI] can be prepared from compounds of formula 5 by halogenation with Cl₂,Br₂, or I₂. Invention compounds of formula 5a [(I) where R^(2a) is F]can be prepared from the formula (I) compounds where R^(2a) is Cl, Br orI by a nucleophilic substitution reaction using a fluoride source, e.g.,KF.

General Method B—Compounds of formula 5 in which R¹, R², Z and E are aspreviously defined can also be prepared via an alternative reactionsequence outlined in General Method “B” below. Thus, dichloropyrimidine8, which is either commercially available or can be made by one skilledin the art according to published procedures (Bagli, J. et al, J. Med.Chem. 1988, 31(4), 814-23), is reacted with a nucleophile of formulaNHR¹Z in a solvent such as alcohol, water, DMF or DMSO to furnishintermediate 9. Such condensations can also be done in a solventcatalyzed by acids such as HCl, H₂SO₄ or an aforementioned base.Compound 9 is reacted with a boronic acid or ester of formula E-B(OR′)₂where R′ is H, alkyl or two R′ may form a ring, under standard Suzukicoupling conditions (such as Pd(PPh₃)₄ orPdCl₂(dppf).CH₂Cl₂/base/solvent) to provide invention compound 5.

General Method C—Invention compounds of formula 5 in which R¹, R² and Eare as defined above, and Z, L′ are defined below can also be preparedvia an alternative reaction sequence outlined in General Method “C”below. Thus, intermediate 4 is reacted with a nucleophile of formula 6using aforementioned conditions (General Method A) to furnishintermediate 10. Compound 10 is treated with an aromatic intermediate offormula 7 in an aprotic solvent and base (such as bases in GeneralMethod A) to furnish invention compounds of formula 5.

General Method D—Invention compounds of formula 13 in which R¹, R² and Zare as defined above, and R^(D) is G2, G12, G23, G24, G30, or benzyl canalso be prepared via a reaction sequence as shown in General Method “D”below. Thus, demethylation of intermediate 11 (General method A or B orC) employing standard conditions (such as BBr₃, Me₃SiI, AlCl₃/EtSH etc.)provides intermediate 12. Subsequently, compound 12 can then undergoalkylation, acylation, or sulfamylation to introduce the R^(D)substituent and provide the compound of formula 13. Standard reactionconditions for these transformations can be used, i.e., a reagent offormula R^(D)-halo in the presence a base. In addition, O-alkylation canbe accomplished using a Mitsunobu reaction (i.e., DEAD/PPh₃) to provideinvention compound 13 where R^(D) is alkyl.

General Method E—Invention compounds of formula 16 and 17 in which R¹,R², G, G″, m, n, and E are as defined above, and M′ is CH or N, can beprepared via a reaction sequence as shown in General Method “E” below.Thus, the cyano group of intermediate 14 can be hydrolyzed and theresulting carboxylic acid can be coupled with an amine such as NHR²⁸R²⁹,a piperidine, or morpholine, under standard conditions to providecompound 16 where G^(E-1) is G21, G25 or G26. Invention compound 17 canbe prepared by reduction of the amide 16 with LiAlH₄ or BH₃, followed byoptional sulfonylation or acylation. Alternatively, compound 17 can beprepared by alkylation or reductive amination of amine 15, which isprepared by reduction of 14 by a reducing agent such as H₂/Pd on C inacetic acid.

General Method F—Invention compounds of formula 17b can be prepared bydisplacement of the halo substituent on the compound of formula 17a witha sulfur, nitrogen or oxygen nucleophile, represented by G^(F-1)-H,e.g., a thiol, ammonia, a mono or dialkylamine, water or an optionallysubstituted alcohol, in the optional presence of a base such astriethylamine, Cs₂CO₃, K₂CO₃, Na₂CO₃, K₃PO₄, Na₃PO₄, NaOH, KOH, NaH,NaNH₂, KNH₂, or a sodium or potassium alkoxide or1,8-diazobicyclo[5.4.0]undec-7-ene (DBU). Thus are prepared compounds offormula (I) in which G^(F-1) is selected from G2, G3, G8, G16, G17, G22,G23, and G24. In addition, compounds of formula 17c may be prepared byacylation or sulfonylation of the compounds of formula 17b where atleast one H may be replaced, using appropriate reagents such as acylhalides or alkylsulfonyl halides, generally in the presence of a base.Thus are prepared compounds of formula (I) in which G^(F-2) is selectedfrom G12, G29, G30 and G31.

General Methods (a-e) for Preparation of Intermediate NHR¹Z

Method a—The compounds of formula 18 in which M, G, G″, m and n are asdefined above, M′ is independently CH or N, and L′ is O or NR⁵ can beconveniently prepared as shown in Method a below. Generally, theintermediate 18 may be prepared by an aromatic substitution reaction ofintermediate 7 and intermediate 6. Thus, aniline or aminopyridine 6 istreated with an aromatic intermediate of formula 7 in an aprotic solventsuch as DMF, DMA, acetonitrile, acetone, dioxane or DMSO and base tofurnish the intermediate of formula 18 (when X=OTf, OMs, OTs see ref.Sammes, P. et al. J. Chem. Soc. Perkin Trans 1, 1988, (12), 3229-31).Compounds of formula 18a can be obtained through reductive amination of18 with an aldehyde under reductive amination conditions such as NaBH₄,NaBH₃CN, or NaBH(OAc)₃.

Method b—Alternatively, compounds of formula 18b, in which M, G, G″, mand n are as defined above, M′ is independently CH or N, and L′ is O,NR⁵ or CH₂, can be conveniently prepared as shown in Method b below.Thus, the aromatic intermediate of formula 20 is deprotonated with anaforementioned base or LDA, n-BuLi, t-BuLi in an aprotic solvent,followed by reaction with intermediate 19 to furnish the intermediate offormula 21. The nitro group of compound 21 can be reduced by one skilledin the art according to published procedures such as catalytichydrogenation, Fe/HOAc and SnCl₂ to provide intermediate 18b.

Method c The 4-substituted aniline compound of formula 25, 26 and 27 inwhich G, G″, m and n are as defined above, P′ is a protecting group, M′is independently CH or N, and R⁶ is H or (C₁-C₃)alkyl can be preparedvia a reaction sequence as outlined in Method c below. Thus,intermediate 22 is treated with acyl chloride 23 under Friedel-Craftsacylation conditions (Lewis acid such as AlCl₃) to furnish theintermediate of formula 24. Compound 24 can be converted to aniline 25by Grignard reaction with R⁶MgBr or reduction with LiAlH₄ followed bydeprotection. Aniline 26 can be obtained by reduction of the carbonylgroup of 24 by methods such as but not limited to N₂H₄/OH⁻, Pd/C/H₂,Et₃SiH/Lewis acid, or NaBH₄/Lewis acid (see ref. Ono, A. et al,Synthesis, 1987, (8), 736-8) or alternatively by formation of a dithianeand subsequent desulfuration with Raney Nickel. In some instances,deprotection of aniline may be necessary to obtain 26. By deprotectionof the amino group of compound 24, the aniline intermediate 27 can alsobe obtained.

Method d The 3-substituted aniline compounds 30, 30a and 31 in which G,G″, m and n are as defined above, M′ is independently CH or N, and R⁶ isH or (C₁-C₃)alkyl can be prepared conveniently via a reaction sequenceas shown in Method d below. Thus, nitration of intermediate 28 employingstandard nitration conditions such as but not limited to HNO₃/H₂SO₄, orNaNO₃/HCl furnishes intermediate 29. Reduction of 29 with a reducingagent such as SnCl₂, Fe/HOAc, or catalytic hydrogenation providesaniline 30. Additionally, compound 29 can be converted to aniline 30a bytreatment with R⁶MgBr or reduction with LiAlH₄ followed by theabove-mentioned reduction conditions. Aniline 31 can be obtained byreduction of the carbonyl group by a method such as but not limited toN₂H₄/NaOH, Pd—C/H2, Et₃SiH/Lewis acid, or NaBH₄/Lewis acid (see ref.Ono, A. et al, Synthesis, 1987, (8), 736-8) or alternatively byformation of dithiane and subsequent desulfuration with Raney Nickel. Insome instances, reduction of the nitro group by an aforementioned methodmay be necessary to obtain aniline 31.

Method e The compounds of formula 36 and 37 in which M, G, G″, m, n, R¹⁰and R¹¹ are as defined above and R^(e) is G2, G16, G23, and G24, can beprepared conveniently via a reaction sequence as shown in Method ebelow. Thus, intermediate pyridine 32 is oxidized by a reagent such asm-CPBA, H₂O₂, CH₃C(O)OOH, or CF₃C(O)OOH to the N-oxide, followed bychlorination with a chlorinating agent such as phosphorous oxychloride,thionyl chloride or phosphorous pentachloride to yield chloropyridine33. Compound 33 can be converted to aniline 36 by treatment with alcoholin the presence of base such as NaH, followed by reduction of the nitrogroup with a reducing agent such as SnCl₂, Fe/H⁺, or catalytichydrogenation. Treatment of compound 33 with amine HNR¹⁰R¹¹ followed byreduction of the nitro group of resulting compound 34 with the abovementioned reagents provides compound 37.

By using these above described methods, the compounds of the inventionmay be prepared. The following specific examples are presented tofurther illustrate the invention described herein, but they should notbe construed as limiting the scope of the invention in any way.

Abbreviations and Acronyms

A comprehensive list of the abbreviations utilized by organic chemistsof ordinary skill in the art appears in the first issue of each volumeof the Journal of Organic Chemistry; this list is typically presented ina table entitled Standard List of Abbreviations. The abbreviationscontained in said list, and all abbreviations utilized by organicchemists of ordinary skill in the art are hereby incorporated byreference.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 67th Ed., 1986-87.

More specifically, when the following abbreviations are used throughoutthis disclosure, they have the following meaning:

-   -   2× two times    -   3× three times    -   AlMe₃ trimethylaluminum    -   Boc t-butoxycarbonyl    -   n-BuLi butyllithium    -   t-BuOK potassium t-butoxide    -   calcd calculated    -   Celite® diatomaceous earth filtering agent, registered trademark        of Celite Corp.    -   CD₃OD methanol-d₄    -   CHCl₃-d chloroform-d    -   d doublet    -   DBU 1,8-diazobicyclo[5.4.0]undec-7-ene    -   DCC dicyclohexylcarbodiimide    -   DEAD diethylazodicarboxylate    -   DIBAH diisobutylaluminum hydride    -   DIEA diisopropylethylamine    -   DMA dimethylacetamide    -   DMAP 4-dimethylaminopyridine    -   DME dimethoxyethane    -   DMF N,N-dimethylformamide    -   DMSO dimethylsulfoxide    -   DMSO-d₆ dimethylsulfoxide-d₆    -   EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride    -   EtSH ethanethiol    -   EtOAc ethyl acetate    -   EtOH ethanol    -   Et₃SiH triethylsilane    -   h hour(s)    -   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate    -   Hex hexanes    -   ¹H NMR proton nuclear magnetic resonance    -   HOAc acetic acid    -   HPLC high performance liquid chromatography    -   LC-MS liquid chromatography/mass spectroscopy    -   LDA lithium diisopropylamide    -   LiHMDS lithium hexamethyldisilazide    -   m multiplet    -   m-CPBA 3-chloroperoxybenzoic acid    -   MeOH methanol    -   min minute(s)    -   Me₃SiI trimethylsilyl iodide    -   MS ES mass spectroscopy with electrospray    -   NaBH(OAc)₃ sodium triacetoxyborohydride    -   OMs O-methanesulfonyl (mesylate)    -   OTs O-p-toluenesulfononyl (tosyl)    -   OTf O-trifluoroacetyl (triflyl)    -   Pd/C palladium on carbon    -   Pd2(dba)₃ tris(dibenzylideneacetone)dipalladium(0)    -   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0)    -   PdCl₂(dppf).CH₂Cl_(2 [)1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)        complex with dichloromethane    -   RT retention time    -   rt room temperature    -   R_(f) TLC Retention factor    -   s singlet    -   t triplet    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   TLC thin layer chromatography

General Analytical Procedures

The structure of representative compounds of this invention wereconfirmed using the following procedures.

Electron impact mass spectra (EI-MS) were obtained with a HewlettPackard 5989A mass spectrometer equipped with a Hewlett Packard 5890 GasChromatograph with a J & W DB-5 column (0.25 uM coating; 30 m×0.25 mm).The ion source was maintained at 250° C. and spectra were scanned from50-800 amu at 2 sec per scan.

High pressure liquid chromatography-electrospray mass spectra (LC-MS)were obtained using either a:

(A) Hewlett-Packard 1100 HPLC equipped with a quaternary pump, avariable wavelength detector set at 254 nm, a YMC pro C-18 column (2×23mm, 120A), and a Finnigan LCQ ion trap mass spectrometer withelectrospray ionization. Spectra were scanned from 120-1200 amu using avariable ion time according to the number of ions in the source. Theeluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% waterin acetonitrile with 0.018% TFA. Gradient elution from 10% B to 95% over3.5 min at a flowrate of 1.0 mL/min is used with an initial hold of 0.5min and a final hold at 95% B of 0.5 min. Total run time is 6.5 min. or

(B) Gilson HPLC system equipped with two Gilson 306 pumps, a Gilson 215Autosampler, a Gilson diode array detector, a YMC Pro C-18 column (2×23mm, 120 A), and a Micromass LCZ single quadrupole mass spectrometer withz-spray electrospray ionization. Spectra were scanned from 120-800 amuover 1.5 seconds. ELSD (Evaporative Light Scattering Detector) data isalso acquired as an analog channel. The eluents were either A: 2%acetonitrile in water with 0.02% TFA or B: 2% water in acetonitrile with0.018% TFA. Gradient elution from 10% B to 90% over 3.5 min at aflowrate of 1.5 mL/min is used with an initial hold of 0.5 min and afinal hold at 90% B of 0.5 min. Total run time is 4.8 min. An extraswitching valve is used for column switching and regeneration.

Routine one-dimensional NMR spectroscopy is performed on 400 MHz VarianMercury-plus spectrometers. The samples were dissolved in deuteratedsolvents obtained from Cambridge Isotope Labs, and transferred to 5 mmID Wilmad NMR tubes. The spectra were acquired at 293 K. The chemicalshifts were recorded on the ppm scale and were referenced to theappropriate solvent signals, such as 2.49 ppm for DMSO-d₆, 1.93 ppm forCD₃CN-d₃, 3.30 ppm for CD₃OD 5.32 ppm for CD₂Cl₂-d₂ and 7.26 ppm forCHCl₃-d for ¹H spectra.

General HPLC Purification Method

Preparative reversed-phase HPLC chromatography was accomplished using aGilson 215 system, typically using a YMC Pro-C18 AS-342 (150×20 mm I.D.)column. Typically, the mobile phase used was a mixture of (A) H₂Ocontaining 0.1% TFA, and (B) acetonitrile. A typical gradient was:

Time Flow [min] A: % B: % [mL/min] 0.50 90.0 10.0 1.0 11.00 0.0 100.01.0 14.00 0.0 100.0 1.0 15.02 100.0 0.0 1.0

EXPERIMENTAL EXAMPLES Preparation of Chloropyrimidine AmineIntermediates Intermediate 1A: Preparation of4-chloro-6-phenylpyrimidin-2-amine

A suspension of guanidine carbonate (3.60 g, 20 mmol) in ethanol (120mL) and toluene (20 mL) was refluxed under nitrogen for 1 h, duringwhich time about 50 mL of solvent was removed by distillation. After themixture was cooled to 45° C., ethyl 3-oxo-3-phenylpropanoate (7.68 g, 40mmol) was added and the solution was heated at reflux overnight. Thedesired product precipitated as a white solid during the reaction. Water(50 mL) was added to the reaction and the mixture was refluxed for anadditional 30 min. After cooling to rt, the mixture was neutralized with1N HCl and placed in the refrigerator for 6 h. The solid was filtered,washed with water followed by ether and dried at 60° C. under vacuum togive the product as white solid (6.45 g, 86%). MS ES: 188 (M+H)⁺, calcd188; RT=0.91 min; TLC (CH₂Cl₂/2M NH₃ in MeOH 95/5) R_(f)=0.10.

A mixture of the above product (6.0 g, 32 mmol) and POCl₃ (100 mL) washeated at reflux for 1 h. The majority of the POCl₃ was removed in vacuoand the residue was diluted with EtOAc and poured over an ice/saturatedNaHCO₃ solution. The aqueous layer was extracted with EtOAc and thecombined organic layers were washed with brine, dried (Na₂SO₄), andconcentrated. The crude organic concentrate was re-crystallized fromEtOAc/ether to give the product 1A as an off-white powder (2.8 g, 43%).MS ES: 206 (M+H)⁺, calcd 206; RT=2.49 min; TLC (CH₂Cl₂/2M NH₃ in MeOH95/5) R_(f)=0.72. (Reference 1: H. L. Skulnick, S. D. Weed, E. E.Edison, H. E. Renis, W. Wierenga, and D. A. Stringfellow, J. Med. Chem.1985, 28, 1854-1869).

Intermediate 1B: Preparation of 4-chloro-6-(2-furyl)pyrimidin-2-amine

The (2-furyl)pyrimidin-2-amine intermediate 1B was prepared by ananalogous method to that described for 1A, starting from guanidinecarbonate and ethyl 3-(2-furyl)-3-oxopropanoate. MS ES: 196 (M+H)⁺,calcd 196, RT=2.13 min.

Intermediate 1C: Preparation of 4-chloro-6-(3-furyl)pyrimidin-2-amine

The (3-furyl)pyrimidin-2-amine intermediate 1C was prepared by ananalogous method to that described for 1A, starting from guanidinecarbonate and ethyl 3-(3-furyl)-3-oxopropanoate. MS ES: 196 (M+H)⁺,calcd 196, RT=2.04 min.

Intermediate 1D: Preparation of 4-chloro-6-(2-thienyl)pyrimidin-2-amine

Step 1: Preparation of ethyl 3-oxo-3-(2-thienyl)propanoate

A solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (12 g, 83.26 mmol) andthiophene-2-carboxylic acid (8.97 g, 70.0 mmol) and DMAP (17.10 g, 140mmol) in methylene chloride (100 mL) was cooled in an ice bath andtreated with a solution of DCC (15.88 g, 76.96 mmol) in methylenechloride (50 mL). The reaction was stirred at rt for 2 h. The resultingprecipitate was filtered and the filtrate was concentrated andre-dissolved in EtOH (400 mL). To this solution was addedp-toluenesulfonic acid (32 g) and the reaction mixture was refluxed for1 h. The solvent was removed in vacuo to afford the crude organicconcentrate which was dissolved in ethyl acetate (1000 mL) and washedwith water (300 mL). The organic layer was washed with saturated aqueoussodium bicarbonate (200 mL), 1N hydrochloric acid (200 mL), saturatedaqueous sodium chloride, dried (Na₂SO₄), and concentrated. The residuewas purified using silica gel column chromatography (0-7% ethyl acetatein hexane) to furnish the desired product as a colorless oil (3.67 g,27%). MS ES 199 (M+H)⁺, calcd 199; RT=2.12 min; TLC (25% ethyl acetatein hexane) R_(f)=0.50.

Step 2: Preparation of title compound (2-thienyl)pyrimidin-2-amine 1D

(2-Thienyl)pyrimidin-2-amine 1D was prepared by an analogous method tothat described for 1A, starting form guanidine carbonate and ethyl3-oxo-3-(2-thienyl)propanoate. MS ES: 212 (M+H), calcd 212, RT=2.42 min;TLC (20% EtOAc-80% hexane): R_(f)=0.29.

Intermediate 1E: Preparation of4-chloro-6-(3-methoxyphenyl)pyrimidin-2-amine

Step 1: Preparation of ethyl 3-oxo-3-(3-methoxyphenyl)propanoate

This material is prepared by a method analogous to that described forpreparation of ethyl 3-oxo-3-(2-thienyl)propanoate in preparation of 1D,starting from 2,2-dimethyl-1,3-dioxane-4,6-dione and 3-methoxybenzoicacid.

Step 2: Preparation of the Title Compound

1E is prepared by a method analogous to that described for 1A, startingfrom guanidine carbonate and ethyl 3-oxo-3-(3-methoxyphenyl)propanoate.

Intermediate 1F: Preparation of4-chloro-6-(4-methoxyphenyl)pyrimidin-2-amine

Step 1: Preparation of ethyl 3-oxo-3-(4-methoxyphenyl)propanoate

This material is prepared by a method analogous to that described forpreparation of ethyl 3-oxo-3-(2-thienyl)propanoate in preparation of 1D,starting from 2,2-dimethyl-1,3-dioxane-4,6-dione and 4-methoxybenzoicacid.

Step 2: Preparation of Title Compound

1F is prepared by a method analogous to that described for 1A, startingfrom guanidine carbonate and ethyl 3-oxo-3-(4-methoxyphenyl)propanoate.

Intermediate 1G: Preparation of4-chloro-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine

Step 1: Preparation of ethyl3-oxo-3-[4-(trifluoromethyl)phenyl]propanoate

This material is prepared by a method analogous to that described forpreparation of ethyl 3-oxo-3-(2-thienyl)propanoate in preparation of 1D,starting from 2,2-dimethyl-1,3-dioxane-4,6-dione and4-(trifluoromethyl)benzoic acid.

Step 2: Preparation of Title Compound

This material is prepared by a method analogous to that described for1A, starting from guanidine carbonate and3-oxo-3-[4-(trifluoromethyl)phenyl]propanoate.

Intermediate 1H: Preparation of4-chloro-6-(4-fluorophenyl)pyrimidin-2-amine

Step 1: Preparation of ethyl 3-(4-fluorophenyl)-3-oxopropanoate

This material is prepared by a method analogous to that described forpreparation of ethyl 3-oxo-3-(2-thienyl)propanoate in preparation of 1D,starting from 2,2-dimethyl-1,3-dioxane-4,6-dione and 4-fluorobenzoicacid.

Step 2: Preparation of title compound

1H is prepared by a method analogous to that described for 1A, startingfrom guanidine carbonate and the product from Step 1, ethyl3-(4-fluorophenyl)-3-oxopropanoate.

Preparation of Substituted Aniline Intermediates Intermediate 2A:Preparation of {4-[(2-ethylpyridin-4-yl)oxy]phenyl}amine

To a −78° C. solution of diisopropylamine (12.1 mL, 86.2 mmol) in THF(20 mL) was added a solution of n-BuLi in hexanes (1.60 M, 26.9 mL, 43.0mmol) dropwise over 5 min. The mixture was stirred for 30 min, then asolution of 4-chloro-picoline (5.00 g, 39.2 mmol) in THF (20 mL) wasadded slowly over 30 min. The reaction mixture was warmed to −60° C. andstirred for 30 min. after which time a solution of methyl iodide (2.44mL, 39.2 mmol) in 10 mL THF was added over a 20 min period. The reactionwas stirred for 30 min at −60° C. and 1.5 h at −30° C. The reaction wasquenched by pouring the mixture into cold brine. The mixture wasextracted with dichloromethane. The organic layers were dried (sodiumsulfate) and concentrated. Vacuum distillation of the residue (10 mm Hg,70-80° C.) furnished 5 g of a 4.5:1 mixture of the desired2-ethyl-4-chloropyridine and the isopropyl analog.

A well stirred, degassed solution of t-BuOK (5.43 g, 44.5 mmol),4-aminophenol (4.16 g, 38.2 mmol) and 2-ethyl-4-chloropyridine (4.5 g,32 mmol, contains 20% isopropyl analog) in dimethylacetamide (100 mL)was heated at 100° C. for 30 h. The reaction mixture was cooled to rtand concentrated in vacuo. The residue was partitioned betweendichloromethane (200 mL) and 0.1 N NaOH (200 mL). The organic phase waswashed with 0.1 N NaOH, dried (Na₂SO₄), and concentrated in vacuo. Thecrude oil was purified by silica gel chromatography (20% EtOAc to 60%EtOAc in hexanes) to provide 3.22 g of the desired ethyl compound 2A and465 mg of the isopropyl analog. MS ES: 215 (M+H)⁺, calcd 215, RT=0.19min.

Intermediate 2B: Preparation of{4-[(2-methylpyridin-4-yl)oxy]phenyl}amine

{4-[(2-Methylpyridin-4-yl)oxy]phenyl}amine (2B) was prepared by a methodanalogous to that described for 4-(3-aminophenoxy)pyridine-2-carboxamide(2C), starting from 4-aminophenol and 4-chloro-2-methylpyridine, MS ES:201 (M+H)⁺, calcd 201, RT=1.01 min.

Intermediate 2C: Preparation of 4-(3-aminophenoxy)pyridine-2-carboxamide

3-Aminophenol (18.12 g, 0.17 mmol) and potassium t-butoxide (12.07 g,0.17 mmol) were suspended in N,N-dimethylformide (350 mL) and stirred atit for 30 min. 2-Amido-4-chloropyridine (20 g, 0.13 mmol) was added andthe mixture was stirred at 90° C. overnight. The reaction mixture wasconcentrated in vacuo. The residue was partitioned between ethyl acetateand water. The aqueous layer was extracted with ethyl acetate. Theorganic layers were combined, dried (Na₂SO₄) and evaporated to dryness.The crude tan solid was recrystallized from ethyl acetate to afford 10.5g (27%) of the desired product 2C. MS ES: 230 (M+H)⁺, calcd 230, RT=1.29min.

Intermediate 2D: Preparation of4-(3-aminophenoxyamino]phenoxy)-N-methyl-pyridine-2-carboxamide

Aniline 2D was prepared by a procedure described in WO 00/42012 (BayerCorporation, ω-Carboxyaryl Substituted Diphenyl Ureas as RAF kinaseInhibitors), starting from 3-aminophenol and4-chloro-2-(N-methylamido)pyridine. MS ES: 244 (M+H)⁺, calcd 244,RT=1.51 min.

Intermediate 2E: Preparation of{4-[(3,5-difluoropyridin-4-yl)oxy]phenyl}amine

{4-[(3,5-Difluoropyridin-4-yl)oxy]phenyl}amine (2E) was prepared by amethod analogous to that described for4-(3-aminophenoxy)pyridine-2-carboxamide (2C), starting from4-aminophenol and 3,4,5-trifluoropyridine, MS ES: 223 (M+H)⁺, calcd 223,RT=0.50 min.

Intermediate 2F: Preparation of4-(4-aminophenoxy)-N-methylpyridine-2-carboxamide

4-(4-Aminophenoxy)-N-methylpyridine-2-carboxamide (2F) was prepared by aprocedure described in WO 00/42012 (Bayer Corporation, ω-CarboxyarylSubstituted Diphenyl Ureas as RAF kinase Inhibitors), starting from4-aminophenol and 4-chloro-2-(N-methylamido)pyridine MS ES: 244 (M+H)⁺,calcd 244, RT=1.16 min.

Intermediate 2G: Preparation of4-(4-amino-3-fluorophenoxy)pyridine-2-carbonitrile

4-(4-Amino-3-fluorophenoxy)pyridine-2-carbonitrile (2G) was prepared bya method analogous to that described for4-(3-aminophenoxy)pyridine-2-carboxamide (2C), starting from4-amino-3-fluorophenol and 4-chloro-2-cyanopyridine, MS ES: 230 (M+H)⁺,calcd 230, RT=2.85 min.

Intermediate 2H: Preparation of4-(4-amino-2-fluorophenoxy)pyridine-2-carbonitrile

4-(4-Amino-2-fluorophenoxy)pyridine-2-carbonitrile (2H) was prepared bya method analogous to that described for4-(3-aminophenoxy)pyridine-2-carboxamide (2C), starting from4-amino-2-fluorophenol and 4-chloro-2-cyanopyridine, MS ES: 230 (M+H)⁺,calcd 230, RT=2.18 min.

Intermediate 2I: Preparation of4-(4-aminophenoxy)pyridine-2-carbonitrile

4-(4-Aminophenoxy)pyridine-2-carbonitrile (2I) was prepared by a methodanalogous to that described for 4-(3-aminophenoxy)pyridine-2-carboxamide(2C), starting from 4-aminophenol and 4-chloro-2-cyanopyridine, MS ES:212 (M+H)⁺, calcd 212, RT=1.23 min.

Intermediate 2J: Preparation of{3-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}-amine

{3-Fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}-amine (2J) was preparedby a method analogous to that described for4-(3-aminophenoxy)pyridine-2-carboxamide (2C), starting from4-amino-2-fluorophenol and 4-chloro-2-cyanopyridine, MS ES: 219 (M+H)⁺,calcd 219, RT=1.07 min.

Intermediate 2K: Preparation of [4-(4-methoxyphenoxy)phenyl]amine

1-Fluoro-4-nitrobenzene (7.76 g, 55.0 mmol) and potassium carbonate(12.0 g, 86.8 mmol) were suspended in anhydrous DMF (100 mL) and stirredat 125° C. for 2 h. 4-Methoxyphenol (6.21 g, 50.0 mmol) was added andthe mixture was stirred vigorously at 125° C. for 4 h. After cooling tort, the reaction mixture was poured into ice-water (1000 mL) and stirredvigorously for 30 min. The resulting yellow solid was collected byvacuum filtration and washed with water to give 11.7 g of the nitrointermediate which was dried in vacuo overnight. This nitro intermediate(8.00 g, 32.6 mmol) was suspended in ethanol (180 mL) and added to aflask charged with 10% Pd/C (0.35 g). The reaction mixture was flushedwith hydrogen gas three times and then stirred at rt under hydrogenatmosphere overnight. The catalyst was removed by filtration and thefiltrate was concentrated. The resulting precipitate was collected byvacuum filtration to give a white solid product (6.76 g, 96%). MS ES 216(M+H)⁺, calcd 216, RT=1.24 min; TLC (25% ethyl acetate-hexane)R_(f)=0.18.

Intermediate 2L: Preparation of4-[4-amino-3-(trifluoromethyl)phenoxy]pyridine-2-carbonitrile

This material is prepared by a method analogous to that described forpreparation of 2C, starting from 4-amino-3-(trifluoromethyl)phenol and4-chloro-2-cyanopyridine.

Intermediate 2M: Preparation of{4-[(2-methylpyrimidin-4-yl)oxy]phenyl}amine

This material is prepared by a method analogous to that described forpreparation of 2C, starting from 4-amino-phenol and4-chloro-2-methylpyrimidine.

Intermediate 2N: Preparation of4-(4-aminophenoxy)-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)pyridine-2-carboxamide

4-(4-Aminophenoxy)-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)pyridine-2-carboxamidewas prepared by a method analogous to that described for4-(3-aminophenoxy)pyridine-2-carboxamide (Intermediate 2C), startingfrom 4-aminophenol andN-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)chloropyridine-2-carboxamideMS ES: 388 (M+H)⁺, calcd 388, RT=3.60 min.

Intermediate 2O: Preparation of 4-(4-fluoro-benzyl)-phenylamine

Step 1. Preparation of (4-fluoro-phenyl)-(4-nitrophenyl)-methanone

To a solution of 4-nitrobenzoyl chloride (2.3 g, 13 mmol) in nitroethane(20 mL) was added aluminum chloride (3.5 g, 26 mmol) followed byfluorobenzene (1.2 mL, 13 mmol). The mixture was stirred at rt for 4 h,then quenched carefully with 6M HCl. The reaction mixture was washedwith dilute aqueous NaOH and brine, dried over sodium sulfate, filtered,and concentrated in vacuo to provide the crude product as a light yellowsolid. The solid was purified by recrystallization from hexanes to give(4-fluoro-phenyl)-(4-nitrophenyl)-methanone (2.0 g, 65%). ¹H NMR(CHCl₃-d) δ 8.41-8.32 (m, 5H), 7.90 (m, 1H), 7.84 (m, 1H), 7.20 (m, 1H).

Step 2. Preparation of 1-fluoro-4(4-nitrobenzyl)benzene

To a solution of (4-fluoro-phenyl)-(4-nitrophenyl)-methanone (2.0 g, 8.2mmol) in dichloromethane (16 mL) at 0° C. was addedtrifluoromethanesulfonic acid (1.4 mL, 16 mmol) in dichloromethane (16mL). A solution of triethylsilane (2 mL, 12 mmol) in dichloromethane (16mL) was subsequently added dropwise, resulting in an exotherm. After 5min, additional trifluoromethanesulfonic acid (1.4 mL, 16 mmol) wasadded, followed by triethylsilane (2.0 mL, 12 mmol). The reactionmixture was stirred at rt for 2 h, then poured into cold saturatedsodium bicarbonate and extracted several times with dichloromethane. Thecombined organic extracts were dried over sodium sulfate andconcentrated in vacuo. Purification by column chromatography elutingwith 0-10% ethyl acetate in hexanes, gave the desired product as a whitesolid (260 mg, 14%). ¹H NMR (CHCl₃-d) δ 8.14 (m, 2H), 7.31 (m, 2H), 7.12(m, 2H), 7.01 (m, 2H), 4.06 (s, 2H).

Step 3. Preparation of the Title Compound

To a solution of the product prepared in Step 2 (260 mg, 1.1 mmol) inethanol (4 mL) and water (1.2 mL) was added iron powder (188 mg, 3.40mmol) and ammonium chloride (36 mg, 0.70 mmol). The reaction was stirredat 85° C. for 2 h, cooled to rt, and filtered through Celite®. Thefiltrate was concentrated then diluted in dichloromethane, washed withwater, and dried over sodium sulfate. The combined organic layers wereconcentrated in vacuo to afford 4-(4-fluoro-benzyl)-phenylamine as lightbrown oil which crystallized upon standing (150 mg, 67%). ¹H NMR(CHCl₃-d) δ 7.11 (m, 2H), 6.95 (m, 4H), 6.62 (m, 2H), 3.85 (s, 2H), 3.59(br s, 2H).

Intermediate 2P: Preparation of4-(2-trifluoromethyl-pyridin-4-ylmethyl)-phenylamine

Step 1. Preparation of(4-nitro-phenyl)-(2-trifluoromethyl-pyridin-4-yl)-acetic acid ethylester

To a solution of ethyl (4-nitrophenyl)acetate (760 mg, 3.6 mmol) in DMF(10 mL) was added 60% sodium hydride (145 mg, 3.6 mmol). The deep purplereaction mixture was stirred at rt for 30 min, then4-fluoro-2-trifluoromethyl-pyridine (500 mg, 3.0 mmol) was added. Afterheating at 70° C. for 2 h, the mixture was poured onto ice water andextracted with ethyl acetate. The organic layers were washed with waterand brine, then dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography, eluting with 10-30% ethylacetate in hexanes, to give(4-nitro-phenyl)-(2-trifluoromethyl-pyridin-4-yl)-acetic acid ethylester as a viscous yellow oil (440 mg, 41%). ¹H NMR (CHCl₃-d) δ 8.70 (d,J=5.1 Hz, 1H), 8.23 (m, 2H), 7.63 (m, 1H), 7.50 (m, 2H), 7.44 (dd,J=5.0, 1.6 Hz, 1H), 5.15 (s, 1H), 4.27 (q, J=7.0 Hz, 2H), 1.30 (t, J=7.1Hz, 3H).

Step 2. Preparation of 4-(4-nitrobenzyl)-2-(trifluoromethyl)pyridine

To a solution of the product prepared in Step 1 (440 mg, 1.24 mmol) inmethanol (13 mL) containing a drop of water, was added powdered LiOH (36mg, 1.5 mmol) and the mixture was stirred at rt overnight. The mixturewas concentrated to remove the methanol, diluted in dichloromethane, andwashed with water. The combined organic extracts were dried over sodiumsulfate, concentrated in vacuo, and purified by column chromatographyeluting with 10-25% ethyl acetate in hexanes to give4-(4-nitrobenzyl)-2-(trifluoromethyl)pyridine as a light yellow solid(100 mg, 29%). ¹H NMR (CHCl₃-d) δ 8.65 (d, J=4.7 Hz, 1H), 8.21 (m, 2H),7.49 (s, 1H), 7.35 (m, 2H), 7.28 (m, 1H), 4.18 (s, 2H).

Step 3. Preparation of the Title Compound

10% Degussa Pd on carbon (15 mg, 0.14 mmol) was flushed with nitrogenthen diluted in ethanol (2 mL). A solution of4-(4-nitrobenzyl)-2-(trifluoromethyl)pyridine (100 mg, 0.35 mmol) inethanol (2 mL) and pyridine (14 mg, 0.18 mmol) was subsequently added,and the mixture was flushed again with nitrogen prior to placing ahydrogen balloon on the flask. The mixture was stirred at rt overnightthen filtered through Celite® and concentrated. The residue wasdissolved in ethyl acetate and filtered through a silica gel plug,eluting with 50-100% ethyl acetate in hexanes, to give4-(2-trifluoromethyl-pyridin-4-ylmethyl)-phenylamine as a clearcolorless oil (76 mg, 85%). ¹H NMR (CHCl₃-d) δ 8.57 (d, J=5.0 Hz, 1H),7.47 (s, 1H), 7.26 (m, 1H), 6.93 (m, 2H), 6.65 (m, 2H), 3.92 (s, 2H),3.57 (br s, 2H).

Intermediate 2Q: Preparation of4-(4-amino-benzyl)-pyridine-2-carbonitrile

Step 1. Preparation of 4-(4-nitro-benzyl)-pyridine-2-carbonitrile

To a solution of 4-(4-nitro-benzyl)-pyridine 1-oxide (1.0 g, 4.3 mmol)in dichloromethane (9 mL) was added trimethylsilyl cyanide (2.3 mL, 17mmol). After 5 min, benzoyl chloride (1.0 mL, 8.7 mmol) was addeddropwise and the mixture was stirred at it for an additional 30 min.Water (10 mL) was carefully added, followed by solid potassium carbonate(2.1 g). After 30 min, the aqueous phase was extracted withdichloromethane and the combined organic layers were dried over sodiumsulfate and concentrated in vacuo. Purification of the residue by columnchromatography, eluting with 5-25% ethyl acetate in hexanes, gave anorange oil. This oil was subsequently triturated with toluene to afford4-(4-nitro-benzyl)-pyridine-2-carbonitrile as a tan solid (353 mg, 34%).¹H NMR (CHCl₃-d) δ 8.63 (d, J=4.8 Hz, 1H), 8.21 (m, 2H), 7.49 (m, 1H),7.32 (m, 3H), 4.15 (s, 2H).

Step 2. Preparation of the Title Compound

10% Degussa Pd on carbon (40 mg, 0.38 mmol) was flushed with nitrogenthen diluted in ethanol (5 mL).4-(4-Nitro-benzyl)-pyridine-2-carbonitrile (250 mg, 1.05 mmol) inethanol (5 mL) and pyridine (42 mg, 0.52 mmol) was subsequently added,and the mixture was flushed again with nitrogen prior to placing ahydrogen balloon on the flask. The mixture was stirred at it overnightthen filtered through Celite® and concentrated. The residue wasdissolved in ethyl acetate and filtered through a silica gel plug,eluting with 50-100% ethyl acetate in hexanes, to give4-(4-amino-benzyl)-pyridine-2-carbonitrile (134 mg, 61%). ¹H NMR(CHCl₃-d) δ 8.55 (d, J=5.2 Hz, 1H), 7.46 (s, 1H), 7.30 (d, J=4.8 Hz,1H), 6.93 (d, J=8.3 Hz, 2H), 6.66 (d, J=8.2 Hz, 2H), 3.91 (s, 2H).

Intermediate 2R: Preparation of 4-(4-aminophenoxy)-2-chloropyridine

4-(4-Aminophenoxy)-2-chloropyridine was prepared by a method analogousto that described for 4-(3-aminophenoxy)pyridine-2-carboxamide (2C),starting from 4-aminophenol and 2,4-dichloropyridine MS ES: 221 (M+H)⁺,calcd 221, RT=0.32 min.

Intermediate 2S: Preparation of4-(2-chloro-pyridin-4-ylmethyl)-phenylamine

4-(2-Chloro-pyridin-4-ylmethyl)-phenylamine was prepared by a methodanalogous to that described for4-(2-trifluoromethyl-pyridin-4-ylmethyl)-phenylamine (Intermediate 2P),starting from ethyl (4-nitrophenyl)acetate and2-chloro-4-nitro-pyridine. ¹H NMR (CHCl₃-d) δ 8.23 (dd, J=5.1, 0.5 Hz,1H), 7.11 (m, 1H), 7.01 (m, 1H), 6.95 (m, 2H), 6.65 (m, 2H), 3.83 (s,2H).

Intermediate 2T: Preparation of 4-[(4-bromopyridin-2-yl)oxy]aniline

A solution of 4-aminophenol (1.86 g, 17.05 mmol) in anhydrous DMF wasadded to a suspension of potassium t-butoxide (2.10 g, 18.75 mmol) inDMF. The mixture was stirred at rt for 1 h. 4-Bromo-2-fluoropyridine(3.00 g, 17.05 mmol) was added into the reaction mixture and it washeated at 90° C. with stirring for 20 h. It was cooled down to rt and100 ml of water was slowly added to quench the reaction. The reactionmixture was concentrated in vacuum to provide a residue which wasextracted with EtOAc (3×) and washed with water (3×). The organic layerwas dried (MgSO₄) and concentrated to give the crude product, which waspurified by flash chromatography (Hexane:EtOAc=6:4) to provide 1.02 g(23%) of the intermediate 2T as a yellow solid. MS ES 265 (M+H)⁺, calc.265, RT=2.52 min; TLC (Hexane/EtOAc=6/4) R_(f)=0.26.

Intermediate 2U: Preparation of4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}aniline

A cold (−5° C.), de-gassed solution of 4-aminophenol (41.6 g, 0.38 mol)in N,N-dimethylacetamide (250 mL) was treated with potassiumtert-butoxide and stirred while warming to 20° C. A solution containing4-fluoro-2-trifluoromethylpyridine (60 g, 0.36 mol) in dimethylacetamide(150 mL) was slowly added and the mixture was stirred at 25° C. for 18h. The reaction mixture was then concentrated in vacuo and the residuewas added to vigorously stirred water (1 L). The precipitated solidswere collected by suction filtration and washed with isopropanol/ether(1:1) followed by ether and hexane. The yellow tan solids were dried toafford 72.8 g (79%) of product. ¹H NMR (DMSO-d₆) δ 5.20 (s, 2H, —NH₂),6.62 (m, 2H), 6.86 (m, 2H), 7.04 (dd, 1H, J=5.6, 2.4 Hz), 7.24 (d, 1H,J=2.4 Hz), 8.54 (d, 1H, 5.7 Hz). MS ES 255 (M+H)⁺, calcd 255, RT=1.66min.

Intermediate 2V: Preparation of methyl4-(4-aminophenoxy)pyridine-2-carboxylate

Step 1. Synthesis of methyl 4-chloropyridine-2-carboxylate HCl salt

Anhydrous DMF (10.0 mL) was slowly added to SOCl₂ (300 mL) at 40-48° C.The solution was stirred at for 10 min., then picolinic acid (100 g, 812mmol) was added over 30 min. The resulting solution was heated at 72° C.(vigorous SO₂ evolution) for 16 h to generate a yellow solid. Theresulting mixture was cooled to rt, diluted with toluene (500 mL) andconcentrated to 200 mL. The toluene addition/concentration process wasrepeated twice. The resulting nearly dry residue was filtered, and thesolids were washed with toluene (50 mL) and dried under high vacuum for4 h to afford 4-chloropyridine-2-carbonyl Chloride HCl salt as anoff-white solid (27.2 g, 16%). This material was set aside.

The red filtrate from above was added to MeOH (200 mL) at a rate whichkept the internal temperature below 55° C. The contents were stirred atrt for 45 min, cooled to 5° C. and treated with Et₂O (200 mL) dropwise.The resulting solids were filtered, washed with Et₂O (200 mL) and driedunder reduced pressure at 35° C. to provide methyl4-chloropyridine-2-carboxylate HCl salt as a white solid (110 g, 65%):mp 108-112° C.; ¹H-NMR (DMSO-d₆) δ 3.88 (s, 3H); 7.82 (dd, J=5.5, 2.2Hz, 1H); 8.08 (d, J=2.2 Hz, 1H); 8.68 (d, J=5.5 Hz, 1H); 10.68 (br s,1H); MS ES 172 (M+H)⁺ calcd 172.

Step 2. Preparation of the Title Compound

Methyl 4-(4-aminophenoxy)pyridine-2-carboxylate was prepared by a methodanalogous to that described for 4-(3-aminophenoxy)pyridine-2-carboxamide(2C), starting from the product of step 1 and 4-aminophenol.

Preparation of Invention Compounds Example 1 Preparation ofN⁴-{4-[(2-ethylpyridin-4-yl)oxy]phenyl}-6-phenyl-pyrimidine-2,4-diamine

Chloropyrimidine 1A (75 mg, 0.35 mmol) and aniline 2A (72 mg, 0.35 mmol)were suspended in water (2 mL) containing concentrated hydrochloric acid(0.1 mL) and stirred at 100° C. for 17 h. After cooling to rt, themixture was neutralized with 1 N aqueous sodium hydroxide and stirredfor 20 min. The precipitate was collected by filtration and purified bysilica gel column chromatography (0-5% methanol-methylene chloride) toafford 43 mg (32%) of the title compound as a yellow solid. ¹H NMR(DMSO-d₆) δ 9.34 (s, 1H), 8.31 (d, 5.7 Hz, 1H), 7.91-7.93 (m, 2H), 7.86(d, J=8.8 Hz, 2H), 7.45-7.47 (m, 3H), 7.07-7.09 (m, 2H), 6.76 (d, J=2.3Hz, 1H), 6.68 (dd, J=5.6 Hz, 1.3 Hz, 1H), 6.49 (s, 1H), 6.37 (b, 2H),2.69 (q, J=7.6 Hz, 2H), 1.19 (t, J=7.4 Hz, 3H), MS ES 384 (M+H)⁺, calcd384, RT=1.87 min; TLC (5/95 v/v methanol-methylene chloride) R_(f)=0.41.The reaction mixture can also be purified by preparative HPLC using anelution gradient from 15% to 85% acetonitrile in water containing 0.1%TFA over 15 min with Phenomenex Luna 5μ C18 150×30 mm column to providethe title compound as its TFA salt.

By dissolving the title compound in an appropriate solvent such as MeOHor dioxane, addition of either 1 N HCl or 1 N methanesulfonic acid, andfiltration, the corresponding HCl or methanesulfonate salt is isolated.

By using the method described for Example 1, and by substitutingappropriate starting materials, Examples 60-68 and 87 were similarlyprepared.

Example 2 Preparation of N⁴-{4-[(2-methylpyridin-4-yl)oxy]phenyl}-6phenylpyrimidine-2,4-diamine

Stating from chloropyrimidine 1A and aniline 2B, this compound wasprepared by a method analogous to that described for Example 1. ¹H NMR(DMSO-d₆) δ 9.31 (s, 1H), 8.25 (d, J=5.7 Hz, 1H), 7.89-7.92 (m, 2H),7.83-7.86 (m, 2H), 7.42-7.48 (m, 3H), 7.04 (d, J=8.9 Hz, 2H), 6.73 (d,J=2.4 Hz, 1H), 6.67-6.69 (m, 1H), 6.47 (s, 1H), 6.34 (s, 2H), 2.37 (s,3H); MS ES: 370 (M+H)⁺, calcd 370, RT=1.41 min; TLC (5/95methanol-methylene chloride) R_(f)=0.33.

Example 3 Preparation of4-{3-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxamide

Starting from chloropyrimidine 1A and aniline 2C, this material wasprepared using a method analogous to that described for Example 1. ¹HNMR (DMSO-d₆) δ 9.43 (s, 1H), 8.50 (d, J=5.6 Hz, 1H), 8.12 (s, 1H),7.88-7.90 (m, 2H), 7.75 (t, J=2.2 Hz, 1H), 7.70 (s, 1H), 7.60 (d, J=8.4Hz, 1H), 7.43-7.46 (m, 4H), 7.38 (t, J=8 Hz, 1H), 7.19 (dd, J=5.5 Hz,1.5 Hz, 1H), 6.75 (dd, J=7.5 Hz, 1.0 Hz, 1H), 6.48 (s, 1H), 6.38 (b,2H); MS ES 399 (M+H)⁺, calcd 399, RT=2.64 min; TLC (5/95methanol-methylene chloride) R_(f)=0.27.

By using the method described for Example 3, and by substitutingappropriate starting materials, Example 69-70 were similarly prepared.

Example 4 Preparation of4-{3-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}-N-methylpyridine-2-carboxamide

Starting from chloropyrimidine 1A and aniline 2D, this material wasprepared using the method similar to Example 1. ¹H NMR (DMSO-d₆) δ 9.43(s, 1H), 8.76-8.79 (m, 1H), 8.50 (d, J=5.8 Hz, 1H), 7.88-7.90 (m, 2H),7.75 (t, J=2.0 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.42-7.47 (m, 4H), 7.38(t, J=8.0 Hz, 1H), 7.17-7.19 (m, 1H), 6.75 (dd, J=8.0 Hz, 1.0 Hz, 1H),6.48 (s, 1H), 6.38 (s, 2H), 2.78 (d, J=4.8 Hz, 3H); MS ES 413 (M+H)⁺,calcd 413, RT=2.13 min; TLC (5/95 methanol-methylene chloride)R_(f)=0.31.

By using the method described for Example 4, and by substitutingappropriate starting materials, Examples 71-74 were similarly prepared.

Example 5 Preparation ofN⁴-{4-[(3,5-difluoropyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine

Staring from chloropyrimidine 1A and aniline 2E, this compound wasprepared by a method analogous to that described for Example 1. ¹H NMR(DMSO-d₆) δ 9.24 (s, 1H), 8.63 (s, 2H), 7.88-7.90 (m, 2H), 7.74 (d,J=9.0 Hz, 2H), 7.43-7.46 (m, 3H), 7.03 (d, J=9.0 Hz, 2H), 6.44 (s, 1H),6.31 (b, 2H); MS ES 392 (M+H)⁺, calcd 392, RT=2.27 min.

Example 6 Preparation of4-(4-amino-3-fluorophenoxy)pyridine-2-carbonitrile hydrochloride

Starting from chloropyrimide 1A and aniline 2G, this material wasprepared by a method analogous to that described for Example 1. Afterthe reaction was complete, the solid was filtered and washed with MeOHto provide the title compound. ¹H NMR (DMSO-d₆) δ 12.99 (s, broad, 1H,10.51 (s, broad, 1H) 8.63 (d, J=6.0 Hz, 1H), 8.07 (s, broad, 1H), 7.88(m, 2H), 7.79 (d, J=2.4 Hz, 1H), 7.66 (m, 3H), 7.45 (dd, J=11.2 Hz, 2.4Hz, 1H), 7.30 (d, J=3.2 Hz, 1H), 7.16 (dd, J=8.8 Hz, 1.6 Hz, 1H), 6.82(s, broad, 1H); MS ES: 399 (M+H)⁺, calcd 399, RT=2.24 min.

Example 7N⁴-{3-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine

Starting from chloropyrimidine 1A and aniline 2H, this material wasprepared by a method analogous to that described for Example 1. ¹H NMR(DMSO-d₆) δ 9.54 (s, 1H), 8.24-8.30 (m, 2H), 7.19 (dd, J=7.6 Hz, 2.4 Hz,2H), 7.44-7.48 (m, 3H), 7.23 (t, J=9.2 Hz, 1H), 6.70-6.76 (m, 2H), 6.49(b, 2H), 2.41 (s, 3H); MS ES 388 (M+H)^(÷), calcd 388, RT 1.70 min.

Example 8 Preparation of4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carbonitrile

Starting from chloropyrimidine 1A and aniline 2I, this material wasprepared by a method analogous to that described for Example 1. ¹H NMR(DMSO-d₆) δ 12.73 (b, 1H), 10.85 (b, 2H), 8.56 (d, J=6.0 Hz, 1H),7.94-7.96 (m, 2H), 7.83-7.85 (m, 2H), 7.71 (d, J=2.4 Hz, 1H), 7.63-7.67(m, 3H), 7.29 (d, J=8.8 Hz, 2H), 7.18-7.21 (m, 1H), 6.65 (s, 1H); MS ES381 (M+H)⁺, calcd 381, RT=2.22 min.

By using the method described for Example 8, and by substitutingappropriate starting materials, Example 75 was similarly prepared.

Example 9 Preparation of4-(3-{[2-amino-6-(3-furyl)pyrimidin-4-yl]amino}phenoxy)-N-methylpyridine-2-carboxamide

Starting from chloropyrimidine 1C and aniline 2D, this material wasprepared by a method analogous to that described for Example 1. ¹H NMR(DMSO-d₆) δ 9.37 (s, 1H), 8.77 (d, J=5.0 Hz, 1H), 8.50 (d, J=5.0 Hz,1H), 8.11 (s, 1H), 7.71-7.74 (m, 2H), 7.56-7.59 (m, 1H), 7.43 (d, J=4.0Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.16-7.18 (m, 1H), 6.79-6.80 (m, 1H),6.72-6.73 (m, 1H), 6.29 (s, 2H), 6.22 (b, 1H), 2.78 (d, J=5.0 Hz, 3H);MS ES 403 (M+H)⁺, calcd 403, RT=1.99 min; TLC (5/95 methanol-methylenechloride) R_(f)=0.27.

Example 10 Preparation of4-(4-{[2-amino-6-(3-furyl)pyrimidin-4-yl]amino}-phenoxy)-N-methylpyridine-2-carboxamide

Starting from chloropyrimidine 1C and aniline 2F, this material wasprepared by the method analogous to that described for Example 1. ¹H NMR(DMSO-d₆) δ 9.31 (s, 1H), 8.76 (d, J=5.0 Hz, 1H), 8.47 (d, J=6.0 Hz,1H), 8.12 (s, 1H), 7.85 (d, J=7.2 Hz, 2H), 7.74 (s, 1H), 7.36 (d, J=3.0Hz, 1H), 7.10-7.14 (m, 3H), 6.81 (s, 1H), 6.18 (s, 2H), 6.23 (s, 1H),2.78 (d, J=5.0 Hz, 3H); MS ES 403 (M+H)⁺, calcd 403, RT=1.94 min; TLC(5/95 methanol-methylene chloride) R_(f)=0.26.

Example 11 Preparation ofN⁴-[4-(4-nitrophenoxy)phenyl]-6-phenylpyrimidine-2,4 diamine

Starting from chloropyrimidine 1A and [4-(4-nitrophenoxy)phenyl]amine,this material was prepared by a method analogous to that described forExample 1. ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.23 (d, J=9.2 Hz, 2H),7.87-7.93 (m, 4H), 7.43-7.48 (m, 3H), 7.08-7.12 (m, 4H), 6.49 (s, 1H),6.37 (b, 2H); MS ES 400 (M+H)⁺, calcd 400, RT=3.01 min; TLC (5/95methanol-methylene chloride) R_(f)=0.67.

Example 12 Preparation ofN⁴-[4-(4-chlorophenoxy)phenyl]-6-phenylpyrimidine-2,4-diamine

Starting from chloropyrimidine 1A and [4-(4-chlorophenoxy)phenyl]amine,this material was prepared by a method analogous to that described forExample 1. ¹H NMR (DMSO-d₆)

9.24 (s, 1H), 7.90 (dd, J=7.8 Hz, 1.8 Hz, 2H), 7.79 (d, J=8.8 Hz, 2H),7.45 (m, 3H), 7.39 (d, J=8.4 Hz, 2H), 6.99 (m, 4H), 6.46 (s, 1H), 6.31(s, 2H); MS ES 389 (M+H)⁺, calcd 389, RT=2.78 min; TLC (CH₂Cl₂/2M NH₃ inMeOH 95/5) R_(f)=0.33

Example 13 Preparation ofN⁴-[4-(4-methoxyphenoxy)phenyl]-6-phenylpyrimidine-2,4-diamine

Starting from chloropyrimidine 1A and aniline 2K, this material wasprepared by a method analogous to that described for Example 1. ¹H NMR(DMSO-d₆)

9.15 (s, 1H), 7.90 (dd, J=9.6 Hz, 1.6 Hz, 2H), 7.70 (m, 2H), 7.44 (m,3H), 6.93 (m, 4H), 6.88 (d, J=8.8 Hz, 2H), 6.43 (s, 1H), 6.27 (s, 2H),3.72 (s, 3H); MS ES 385 (M+H)⁺, calcd 385, RT=2.48 min.

Example 14 Preparation of4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]-2-fluorophenoxy}pyridine-2-carbonitrile

This material is prepared by a method analogous to that described inExample 1, starting from 2H and 1A.

Example 15 Preparation of 4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]-3(trifluoromethyl)phenoxy}pyridine-2-carbonitrile

This material is prepared by a method analogous to that described inExample 1, starting from 2L and 1A.

Example 16 Preparation ofN⁴-{4-[(2-methylpyrimidin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine

This material is prepared by a method analogous to that described inExample 1, starting from 2M and 1A.

Example 17 Preparation ofN⁴-{4-[(2-methylpyridin-4-yl)oxy]phenyl}-6-[4-(2-pyrrolidin-1-ylethoxy)phenyl]pyrimidine-2,4-diamine

Step 1: Preparation of6-(4-methoxyphenyl)-N⁴-{4-[(2-methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine

This material is prepared by a method analogous to that described forExample 1, starting from 1F and 2B.

Step 2: Preparation of4-[2-amino-6-({4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]phenol

The intermediate from Step 1 above is treated with BBr₃ in methylenechloride at 0° C. for 12 h. After work-up and purification by apublished procedure (J. F. W. McOmie and D. E. West, Org. Synth.,Collect. Vol. V, 412 (1973)), the desired compound is obtained.

Step 3: Preparation of6-[4-(2-bromoethoxy)phenyl]-N⁴-{4-[(2-methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine

To a solution of Step 2 product (1 equiv) in DMF is added1,2-dibromoethane (1 equiv) and K₂CO₃ (3 equiv). The mixture is refluxedovernight. After cooling to rt, the mixture is diluted with EtOAc andwashed sequentially with 1N NaOH, water and brine. The organic layer isdried (Na₂SO₄) and concentrated to afford a crude product which is to beused in next step without further purification.

Step 4: Preparation of the Title Compound

A mixture of the product from Step 3 (1 equiv), pyrrolidine (2 equiv)and K₂CO₃ (8 equiv) in DMF is stirred at 65° C. overnight. The solventis removed and the residue is dissolved in EtOAc. The organic solutionis washed with water, dried, and evaporated to dryness. The residue ispurified by chromatography on a silica column to afford the titlecompound.

By using the method described for Example 17, and by substitutingappropriate starting materials, Examples 76-77 are similarly prepared.

Example 18 Preparation of4-[4-({2-amino-6-[4-(2-piperidin-1-ylethoxy)phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2-carbonitrile

This is prepared by a method analogous to that described for Example 17,starting from 1F, 2I and using piperidine in step 4.

Example 19 Preparation of methyl4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxylate

Starting from chloropyrimidine 1A and aniline 2V, this material wasprepared using a method analogous to that described for Example 1. ¹HNMR (DMSO-d₆) δ 9.37 (s, 1H), 8.52 (d, 1H), 7.85 (m, 4H), 7.41 (m, 4H),7.16 (m, 3H), 6.45 (s, 1H), 6.36 (s, 2H), 3.79 (s, 3H); MS ES 414(M+H)⁺, calcd 414, RT=2.16 min.

Example 20 Preparation of4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxylicacid

A solution containing the4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carbonitrile(20 g, 0.05 mol, Example 8) in concentrated sulfuric acid (150 mL) washeated at 70° C. for 12 h. The reaction mixture was then cooled to −40°C. and water (30 mL) was added, followed by heating at 70° C. for 12 h.The solution was cooled to rt and poured into vigorously stirred icewater (2 L) and stirring was continued for 2 h. The solids were thencollected by suction filtration, washed with water (500 mL) and dried byair suction. The slightly damp material was then dissolved in a minimumvolume of hot (90° C.) N,N-dimethylformamide and triethylamine was addeduntil the mixture tested slightly acidic. The cooled solution was thenpoured into ice water (2 L), stirred for 0.5-1 h and the precipitatedmaterial was collected by suction filtration. The filter cake was washedwith water, followed by isopropanol, diethyl ether, and finally hexane.Air-drying sequentially afforded the carboxylic acid as an off-whitesolid, 18.5 g (90%). ¹H NMR (DMSO-d₆) δ 9.40 (s, 1H). 8.53 (d, 1H, J=5.8Hz), 7.90 (m, 4H), 7.46 (m, 3H), 7.40 (d, 1H, J=7.1 Hz), 7.16 (m, 1H),7.13 (d, 2H, J=9.1 Hz), 6.50 (s, 1H), 6.40 (s, 2H), 3.30 (br s, 1H), MSES 400 (M+H)⁺, calcd 400, RT=1.71 min.

The HCl salt of the title compound, (Example 78) was prepared byaddition of Example 20 to a 1N HCl.

Example 21 Preparation ofN⁴-(4-{[2-(morpholin-4-ylcarbonyl)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine

To a solution of4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxylicacid (Example 20, 0.15 g, 0.38 mmol) in dry DMA (3 mL) was added HATU(0.14 g, 0.38 mmol) and DIEA (0.15 g, 1.13 mmol). The solution wasstirred at rt for 0.5 h, followed by addition of morpholine (0.16 g,1.88 mmol). The resulting solution was stirred at rt overnight, followedby prep-HPLC separation to give 77 mg (35%) pure product. ¹H NMR(DMSO-d₆)

10.79 (s, 1H), 8.40 (s, 1H), 7.85 (m, 2H), 7.74 (m, 2H), 7.60 (m, 3H),7.21 (m, 2H), 7.00 (m, 2H), 6.59 (s, 1H), 3.49 (m, 8H); MS ES 469(M+H)⁺, calcd 469.

Example 22 Preparation of4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}-N,N-dimethylpyridine-2-carboxamide

This material is prepared by a method analogous to that described forExample 21, starting from4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxylicacid and dimethylamine.

Example 23 Preparation of4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}-N-(2-methoxyethyl)pyridine-2-carboxamide

This material was prepared by a method analogous to that described forExample 21, starting from4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxylicacid and 2-methoxyethylamine.

By using the method described for Example 23, and by substitutingappropriate starting materials, Examples 79-82 were similarly prepared.

Example 24 Preparation of4-[4-({2-amino-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)phenoxy]-N-(2-methoxyethyl)pyridine-2-carboxamide

Step 1: Preparation of4-[4-({2-amino-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2-carboxylicacid

This material is prepared by methods analogous to that described forExample 1 and Example 20, starting from 2I and 1G.

Step 2: Preparation of the Title Compound

This material is prepared by a method analogous to that described forExample 21 starting from 2-methoxyethylamine and 4-[4-({2-amino-6(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2-carboxylicacid.

Example 25 Preparation of4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}-N-(2-methoxyethyl)-N-methylpyridine-2-carboxamide

This material is prepared by a method analogous to that described forExample 21, starting from4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxylicacid and 2-methoxyethyl-N-methyl amine.

Example 26 Preparation ofN⁴-[4-({2-[(4-methylpiperazin-1-yl)carbonyl]pyridin-4-yl}oxy)phenyl]-6-phenylpyrimidine-2,4-diamine

This material is prepared by a method analogous to that described forExample 21, starting from4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxylicacid (Example 20) and 1-methylpiperizine. ¹H NMR (DMSO-d₆) δ 10.85 (s,1H), 10.19 (s, 1H), 8.42 (d, 1H), 7.90 (m, 2H), 7.74 (m, 3H), 7.59 (m,4H), 7.22 (m, 3H), 7.06 (m, 2H), 6.60 (s, 1H), 4.51 (m, 1H), 4.08 (m,1H), 3.45 (m, 3H), 3.17 (m, 3H), 2.78 (s, 3H); MS ES 482 (M+H)⁺, calcd482, RT=1.86 min.

Example 27 Preparation ofN⁴-{4-[(2-{[(2-methoxyethyl)amino]methyl}pyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine

A solution of4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}-N-(2-methoxyethyl)pyridine-2-carboxamidefrom Example 23 (50 mmol) in anhydrous THF (50 mL) is added in portionsto a pre-cooled in ice-bath solution of lithium aluminum hydride (100mmol, 1.0 M in THF) in anhydrous THF (150 mL). The reaction is stirredat 0° C. for 30 min until evolution of hydrogen subsides. The reactionmixture is refluxed under nitrogen for 48 h. The mixture is brought to5-10° C. and carefully quenched with water (3.8 mL), 15% NaOH (3.8 mL)and water (12 mL). The mixture is extracted with EtOAc and the organiclayer is dried and concentrated to give a crude product which ispurified by chromatography on a silica column to give the titlecompound.

(Reference: Org. Synth. Collect., 1988, Vol. VI, 382-385)

Example 28 Preparation of6-(4-fluorophenyl)-N⁴-(4-{[2-(piperidin-1-ylcarbonyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine

Step 1: Preparation of4-(4-{[2-amino-6-(4-fluorophenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxylicacid

This material is prepared by a method analogous to that described forExamples 1 and 20 starting from 1H and 2I.

Step 2: Preparation of6-(4-methoxyphenyl)-N⁴-(4-{[2-(morpholin-4-ylcarbonyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine

This material is prepared by a method analogous to that described forExample 21, starting from6-(4-fluorophenyl)-N⁴-[4-(pyridin-4-yloxy)phenyl]pyrimidine-2,4-diamineand piperidine.

Step 3: Preparation of the Title Compound

This material is prepared by a method analogous to that described forExample 27, starting from6-(4-methoxyphenyl)-N⁴-(4-{[2-(morpholin-4-ylcarbonyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine.

Example 29 Preparation of6-(4-methoxyphenyl)-N⁴-(4-{[2-(morpholin-4-ylmethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine

Step 1: Preparation of4-(4-{[2-amino-6-(4-methoxyphenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxylicacid

This material is prepared by a method analogous to that described forExamples 1 and 20, starting from 1F and 2I.

Step 2: Preparation of6-(4-methoxyphenyl)-N⁴-(4-{[2-(morpholin-4-ylcarbonyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine

This material is prepared by a method analogous to that described forExample 21, starting from the product from step 1.

Step 3: Preparation of Title Compound

This material is prepared by a method analogous to that described forExample 27, starting from the product of step 2.

Example 30 Preparation ofN²-ethyl-6-(3-methoxy-phenyl)-N⁴-[4-(2-trifluoromethyl-pyridin-4-yloxy)-phenyl]-pyrimidine-2,4-diamine

Step 1: Preparation of 2,4-dichloro-6-(3-methoxy-phenyl)-pyrimidine

Trichloropyrimidine (11.83 g, 64.49 mmol) was added to a solution of3-methoxyphenylboronic acid (9.8 g, 64.49 mmol) in a solvent mixture ofethanol (30 mL), toluene (30 mL) and 2M aqueous sodium bicarbonate (96.7mL) at rt. The resulting mixture was degassed under vacuum for severalmin before the flask was purged with nitrogen.Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (2.4 g, 3.22 mmol) was added and theresulting mixture was heated for 3 h at 50° C. The cooled reactionmixture was filtered through a silica gel pad and the pad was washedwith acetone. The filtrated was evaporated under reduced pressure. Thecrude material was purified by column chromatography eluting with agradient of 0 to 45% ethyl acetate/hexanes to give2,4-dichloro-6-(3-methoxy-phenyl)-pyrimidine as a white solid (14.4 g,65.4%). MS ES 255 (M+H)⁺, calcd 255, RT=3.35 min.

Step 2: Preparation of[2-chloro-6-(3-methoxy-phenyl)-pyrimidin-4-yl]-[4-(2-trifluoromethyl-pyridin-4-yloxy)-phenyl]-amine

2,4-Dichloro-6-(3-methoxy-phenyl)-pyrimidine (1.0 g, 3.92 mmol) and4-(2-trifluoromethyl-pyridin-4-yloxy)-phenylamine Intermediate 2U (1.0g, 3.92 mmol) were suspended in a mixture of isopropanol/water 2:8 (40mL). The reaction mixture was heated at reflux for 24 h at which pointthe TLC showed a completed reaction. The reaction mixture was filteredwith a fritted glass funnel. The crude residue was purified by HPLCeluting with a gradient of 0 to 71% acetonitrile/water containing 0.1%TFA in both solvents. The TFA salt of[2-chloro-6-(3-methoxy-phenyl)-pyrimidin-4-yl]-[4-(2-trifluoromethyl-pyridin-4-yloxy)-phenyl]-aminewas obtained as a yellow oil which solidified on standing. (926 mg,50.1%). MS ES 473 (M+H)⁺, calcd 473, RT=3.98 min.

Step 3: Preparation of the title compound:N²-ethyl-6-(3-methoxy-phenyl)-N⁴-[4-(2-trifluoromethyl-pyridin-4-yloxy)-phenyl]-pyrimidine-2,4-diamine

[2-Chloro-6-(3-methoxy-phenyl)-pyrimidin-4-yl]-[4-(2-trifluoromethyl-pyridin-4-yloxy)-phenyl]-amine(100 mg, 0.21 mmol) and ethylamine (2M THF, 1 mL) were dissolved inn-butanol (3 mL) and the reaction mixture was heated at 120° C.overnight. The reaction mixture were evaporated under vacuum, and thecrude residue was purified by HPLC eluting with a gradient of 10 to 85%acetonitrile/water containing 0.1% TFA in both solvents. The TFA salt ofN²-Ethyl-6-(3-methoxy-phenyl)-N⁴-[4-(2-trifluoromethyl-pyridin-4-yloxy)-phenyl]-pyrimidine-2,4-diamine(13.9 mg, 11%) was obtained as a beige solid. ¹H NMR (acetone-d₆) δ10.36 (br, 1H), 10.06 (Br, 1H), 8.62 (d, J=6 Hz, 1H), 8.00 (br, 1H),7.53-7.51 (m, 1H), 7.47-7.31 (m, 2H), 7.19-7.12 (m, 3H), 6.66 (s, 1H),3.94 (s, 3H), 3.59-3.56 (m, 2H), 1.31 (t, J=7 Hz, 3H). MS ES 482 (M+H)⁺,calcd 482, RT=2.83 min.

Example 31 Preparation of4-[4-(2-amino-5-bromo-6-phenyl-pyrimidin-4-ylamino)-phenoxy]-pyridine-2-carbonitrile

To a solution of4-[4-(2-amino-6-phenyl-pyrimidin-4-ylamino)-phenoxy]-pyridine-2-carbonitrile(Example 8, 200 mg, 0.53 mmol) and sodium acetate (146.6 mg, 459.8 mmol)in acetic acid (4 mL) at rt was added bromine (84 mg, 0.53 mmol). Thereaction was allowed to stand for 2 h after which time dichloromethane(20 mL) was added followed by water (20 mL). The phases were separatedand the organic layer was washed with a saturated aqueous bicarbonatesolution. The combined organic extracts were dried over MgSO₄ and thenevaporated under vacuum. The crude material was purified by columnchromatography eluting with a gradient of 0 to 60% AcOEt/Hexanes to give4-[4-(2-Amino-5-bromo-6-phenyl-pyrimidin-4-ylamino)-phenoxy]-pyridine-2-carbonitrileas an orange solid (200 mg, 83%). ¹H NMR (DMSO d₆) δ 8.58 (d, J=5 Hz,1H, 8.50 (Br, 1H), 7.90-7.86 (m, 2H), 7.67 (d, J=2 Hz, 1H), 7.54-7.51(m, 2H), 7.47-7.41 (m, 3H), 7.20-7.16 (m, 3H), 6.57 (Br, 2H). MS ES 459(M+H)⁺, calcd 459, RT=2.85 min.

Example 32 Preparation ofN⁴-{4-[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-yloxy]-phenyl}-6-phenyl-pyrimidine-2,4-diamine

N⁴-[4-(2-chloro-pyridin-4-yloxy)-phenyl]-6-phenyl-pyrimidine-2,4-diamine(Example 48, 75 mg, 0.19 mmol) was dissolved in toluene (1.5 mL).2-Morpholin-4-yl-ethanol (61 mg, 0.46 mmol), powdered KOH (22 mg, 0.38mmol), and 18-crown-6 (20 mg, 0.08 mmol) were subsequently added. Themixture was stirred at 90° C. overnight, after which time it was dilutedwith water and extracted with both ethyl acetate and dichloromethane.The combined organic extracts were concentrated and the residue waspurified by prep HPLC to give the title compound (14 mg, 15%). ¹H NMR(DMSO-d₆) δ 10.79 (br s, 1H), 9.99 (br s, 1H), 8.08 (d, J=5.8 Hz, 1H),7.90 (m, 2H), 7.77 (dd, J=7.6, 2.0 Hz, 2H), 7.64 (m, 3H), 7.21 (d, J=8.9Hz, 2H), 6.69 (dd, J=5.8, 2.1 Hz, 1H), 6.60 (s, 1H), 6.22 (d, J=2.2 Hz,1H), 4.57 (t, J=5.1 Hz, 2H), 3.96 (m, 2H), 3.68 (m, 2H), 3.50 (m, 4H),3.15 (m, 2H); MS ES: 485 (M+H)⁺, calcd 485, RT=1.96 min.

By using the method described for Example 32, and by substitutingappropriate starting materials, Examples 83-86 were similarly prepared.

Example 33 Preparation of6-phenyl-N⁴-[4-(2-trifluoromethyl-pyridin-4-ylmethyl)-phenyl]-pyrimidine-2,4-diamine

Starting from chloropyrimidine 1A and aniline 2P, this material wasprepared using a method analogous to that described for Example 1. ¹HNMR (DMSO-d₆) δ 12.90 (br s, 1H), 10.82 (br s, 1H), 8.64 (d, J=5.1 Hz,1H), 7.83 (m, 3H), 7.74 (m, 2H), 7.64 (m, 4H), 7.31 (d, J=8.3 Hz, 2H),6.67 (br s, 1H), 4.11 (s, 2H); MS ES: 422 (M+H)⁺, calcd 422, RT=2.51min.

Example 34 Preparation ofN⁴-[4-(2-chloro-pyridin-4-ylmethyl)-phenyl)-6-phenyl-pyrimidine-2,4-diamine

Starting from chloropyrimidine 1A and aniline 2S, this material wasprepared using a method analogous to that described for Example 1. ¹HNMR (DMSO-d₆) δ 12.80 (br s, 1H), 10.74 (br s, 1H), 8.29 (dd, J=5.4, 0.6Hz, 1H), 7.83 (m, 2H), 7.67 (m, 2H), 7.63 (m, 3H), 7.41 (m, 1H), 7.30(m, 3H), 6.61 (br s, 1H), 3.98 (s, 2H); MS ES: 388 (M+H)⁺, calcd 388,RT=2.38 min.

Example 35 Preparation of4-[4-(2-amino-6-phenyl-pyrimidin-4-ylamino)-benzyl]-pyridine-2-carbonitrile

Starting from chloropyrimidine 1A and Intermediate 2Q, this material wasprepared using a method analogous to that described for Example 1. ¹HNMR (DMSO-d₆) δ 12.74 (br s, 1H), 10.73 (br s, 1H), 8.63 (d, J=4.9 Hz,1H), 7.96 (s, 1H), 7.82 (m, 2H), 7.72 (m, 2H), 7.61 (m, 4H), 7.30 (d,J=7.9 Hz, 2H), 6.61 (s, 1H), 4.05 (s, 2H); MS ES: 379 (M+H)⁺, calcd 379,RT=2.35 min.

By using the method described for Example 35, and by substitutingappropriate starting materials, Examples 88-91 were similarly prepared.

Example 36 Preparation ofN⁴-[4-(2-aminomethyl-pyridin-4-ylmethyl)-phenyl]-6-phenyl-pyrimidine-2,4-diamine

10% Degussa Pd on carbon (15 mg, 0.14 mmol) was flushed with nitrogenthen diluted in methanol (1 mL).4-[4-(2-amino-6-phenyl-pyrimidin-4-ylamino)-benzyl]-pyridine-2-carbonitrile(Example 35, 90 mg, 0.24 mmol) in methanol (2 mL) and concentrated HCl(0.03 mL) were subsequently added, and the mixture was flushed againwith nitrogen prior to placing a hydrogen balloon on the flask. Themixture was stirred at rt for 3 h then filtered through Celite® andconcentrated. The residue was purified by prep HPLC to giveN⁴-[4-(2-aminomethyl-pyridin-4-ylmethyl)-phenyl]-6-phenyl-pyrimidine-2,4-diamine(10 mg, 11%). ¹H NMR (CD₃OD) δ 8.50 (d, J=5.3 Hz, 1H), 7.76 (m, 4H),7.63 (m, 3H), 7.28 (m, 4H), 6.53 (s, 1H), 4.22 (s, 2H), 4.05 (s, 2H); MSES: 383 (M+H)⁺, calcd 383, RT=1.84 min.

Example 37 Preparation of6-phenyl-N⁴-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine

Starting from chloropyrimidine 1A and4-(2-trifluoromethyl-pyridin-4-yloxy)-phenylamine 2U, the title compoundwas prepared using a method analogous to that described for Example 1.¹H NMR (CD₃OD) δ ppm 6.59 (1H, s), 7.16 (1H, dd, J=5.6, 2.4 Hz),7.29-7.33 (2H, m), 7.42 (1H, d, J=2.4 Hz), 7.61-7.67 (3H, m), 7.75-7.79(2H, m), 7.94 (2H, s), 8.63 (1H, d, J=5.7 Hz), 10.79 (1H, s); MS ES 424(M+H)⁺, calcd 424, RT=2.48 min.

Example 38 Preparation ofN⁴-(4-{[1-oxido-2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine

To a solution of6-phenyl-N⁴-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine(0.10 g, 0.24 mmol, Example 37) in CHCl₃, m-CPBA (77%, 0.053 g, 0.24mmol) was added and the mixture was stirred at rt overnight. Solvent wasremoved in vacuo, and the residue was taken up in DMF and purified byprep-HPLC to provide 11 mg of an off-white solid (11%). ¹H NMR (DMSO-d₆)δ10.20 (s, 1H), 8.64 (d, J=5.7 Hz, 1H), 7.93 (s, 1H), 7.86-7.92 (m, 2H),7.52-7.56 (m, 2H), 7.41-7.49 (m, 5H), 7.30-7.39 (m, 2H), 7.24 (dd, J=5.7Hz, 1H), 6.71 (s, 1H). MS ES 440 (M+H)⁺, calcd 440, RT=2.97 min.

Example 39N⁴-(4-{[2-(aminomethyl)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine

A mixture containing of4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carbonitrile(3.2 g, 8.4 mmol, Example 8) and 10% palladium on carbon catalyst (0.75g, Degussa) in glacial acetic acid (100 mL) was shaken on a Parrhydrogenation apparatus (3 atm H₂) until hydrogen consumption ceased.The suspension was filtered through diatomaceous earth and the filtratewas concentrated in vacuo. The residue was dissolved inN,N-dimethylformamide and treated with triethylamine until basic, thenwas added to vigorously stirred ice water. The precipitated solids werecollected by suction filtration and washed with water, isopropanol,diethyl ether and finally hexane. The product was dried by air suctionto afford a tan powder, 2.36 g (73%). ¹H NMR (DMSO-d₆) δ ppm 9.39 (s,1H), 8.30 (m, 1H), 7.89 (m, 4H), 7.44 (m, 3H), 7.05 (m, 2H), 6.96 (dm,1H), 6.69 (dm, 1H), 6.51 (s, 1H), 6.36 (s, 2H), 4.16 (d, 0.5H, J=5.8 Hz,CH ₂NH₂), 3.73 (s, 1.5H, CH ₂NH₂), 3.28 (br s, 2H, NH₂), MS ES 385(M+H)⁺, calcd 385 RT=1.75 min.

The TFA salt (Example 92) was obtained by preparative HPLC of the abovereaction mixture.

Example 40 Preparation ofN-[(4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]-phenoxy}pyridin-2-yl)methyl]methanesulfonamide

Methanesulfonyl chloride (0.040 mL, 0.52 mmol) was added to a solutionofN⁴-(4-{[2-(aminomethyl)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine(Example 39, 0.20 g, 0.52 mmol) and DMAP (0.064 g, 0.52 mmol) inpyridine (8.0 mL) at 0° C. The mixture was allowed to warm to rt and wasstirred overnight. The mixture was concentrated in vacuo and the residuewas taken up in DMF and purified by prep-HPLC to provide 82 mg of anoff-white solid (27%). ¹H NMR (CD₃OD) δ ppm 8.57 (1H, d, J=6.8 Hz), 8.00(2H, s), 7.77-7.80 (2H, m), 7.63 (3H, d, J=7.4 Hz), 7.42 (1H, d, J=2.5Hz), 7.29-7.33 (3H, m), 6.58 (1H, s), 4.54 (2H, s), 3.04 (3H, s); MS ES463 (M+H)⁺, calcd 463, RT=1.17 min.

By using the method described for Example 40, and by substitutingappropriate starting materials, Examples 93-98 were similarly prepared.

Example 41 Preparation ofN-[(4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl]-4-fluorobenzamide

N⁴-(4-{[2-(Aminomethyl)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine(50 mg, 0.13 mmol, Example 39) and 4-fluorobenzoyl chloride (20.6 mg,0.13 mmol) were suspended in THF (1 mL) and stirred at rt for 24 h. TLCand LC-MS indicated the reaction was completed. The mixture wasextracted with EtOAc and washed with 1N aqueous sodium hydroxidesolution (2×) and H₂O (3×). The organic layer was dried and concentratedto give 68 mg of the crude product. The residue was purified by Prep-TLC(CH₃OH:EtOAc=2:8) to obtain 38 mg (58%) of the title product as ayellowish oil. ¹H NMR (CD₃OD) δ 8.34 (d, 1H), 7.82 (m, 4H), 7.78 (d,2H), 7.44 (m, 3H), 7.15 (t, 2H), 7.02 (d, 2H), 6.85 (d, 1H), 6.82 (s,1H), 6.42 (s, 1H), 4.59 (s, 2H); MS ES 507 (M+H)⁺, calcd 507, RT=2.50min; TLC (MeOH/EtOAc=20/80) R_(f)=0.57.

Example 42 Preparation ofN′-[(4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl]-N,N-diethylurea

N⁴-(4-{[2-(Aminomethyl)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine(50 mg, 0.13 mmol, Example 39) and diethylcarbamyl chloride (20.6 mg,0.13 mmol) were suspended in THF (1 mL) and stirred at rt for 24 h. TLCand LC-MS indicated that the reaction was complete. The mixture wasextracted with EtOAc and washed with 1N aqueous sodium hydroxidesolution (2×) and H₂O (3×). The organic layer was dried and concentratedto give 72 mg of the crude product. The residue was purified by Prep-TLC(CH₃OH:EtOAc=2:8) to obtain 40 mg (63%) of the title product as ayellowish oil. ¹H NMR (CD₃OD) δ 8.28 (d, 1H), 7.84 (m, 3H), 7.81 (s,1H), 7.48 (m, 3H), 7.05 (d, 2H), 6.84 (m, 1H), 6.75 (s, 1H), 6.44 (s,1H), 4.39 (s, 2H), 3.23 (m, 4H), 1.20 (t, 6H); MS ES 484 (M+H)⁺, calcd484, RT=2.37 min; TLC (MeOH/EtOAc=20/80) R_(f)=0.4

By using the method described for Example 42, and by substitutingappropriate starting materials, Examples 99-104 were similarly prepared.

Example 43 Preparation ofN⁴-[4-({4-[(2S)-(+)-2-(methoxymethyl)pyrrolidin-1-yl]pyridin-2-yl}oxy)phenyl]-6-phenylpyrimidine-2,4-diamine

N⁴-{4-[(4-Bromopyridin-2-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine(75 mg, 0.17 mmol, was prepared by the method of Example 1 using andIntermediates 2T and 1A as starting materials.N⁴-[4-(4-bromo-pyridin-2-yloxy)-phenyl]-6-phenyl-pyrimidine-2,4-diamine,was then combined with (S)-(+)-2-(methoxymethyl)pyrrolidine (99.5 mg,0.86 mmol) in a 5-mL reaction flask and heated at 108° C. with stirringfor 24 h. TLC and LC-MS indicated that the reaction was complete. Aftercooling to rt, the reaction mixture was extracted with EtOAc and washedwith 1N aqueous sodium hydroxide solution (2×) and H₂O (3×). The organiclayer was dried and concentrated to give 75 mg of the crude product. Theresidue was purified by Prep-TLC (CH₃OH:EtOAc=2:8) to obtain 32 mg (40%)of the title product as a yellowish oil. ¹H NMR (CD₃OD) δ 7.82 (m, 2H),7.70 (m, 3H), 7.41 (m, 3H), 7.04 (d, 2H), 6.41 (m, 2H), 5.94 (s, 1H),3.86 (s, 1H), 3.38 (m, 2H), 3.30 (m, 3H), 3.18 (m, 1H), 2.01 (m, 4H),1.30 (m, 1H); MS ES 469 (M+H)⁺, calcd 469, RT=1.9 min; TLC (EtOAc)R_(f)=0.2.

By using the method described for Example 43, and by substitutingappropriate starting materials, Examples 105-109 were similarlyprepared.

Example 44 Preparation ofN⁴-[4-({2-[(isopropylamino)methyl]pyridin-4-yl}oxy)phenyl]-6-phenylpyrimidine-2,4-diamine

Acetone (11.51 mg, 0.20 mmol),N⁴-(4-{[2-(aminomethyl)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine(80 mg, 0.21 mmol, Example 39) and titanium (IV) methoxide (68.2 mg,0.40 mmol) were suspended in CH₂Cl₂ (5 mL) and stirred at rt for 24 h.Sodium triacetoxyborohydride (105 mg, 0.50 mmol) was added into thereaction mixture and the mixture was stirred at it for another 24 h. Themixture was filtered through a Celite® pad and washed with CH₂Cl₂. Asmall amount of Celite® was added to the filtrate and 5 mL of water wasadded to quench the reaction. After it was stirred for 20 min, theCH₂Cl₂ was removed in vacuo. The residue was taken up in ethyl acetateand washed with 1N NaOH (2×) and water (3×). The organic layer wasconcentrated and purified by Prep-TLC (MeOH) to give 36 mg (42.2%) ofthe title product as a white solid. ¹H NMR (CD₃OD) δ 8.35 (d, 1H), 7.82(d, 2H), 7.00 (d, 2H), 7.44 (m, 3H), 7.08 (m, 2H), 7.01 (s, 1H), 6.82(m, 1H), 6.46 (s, 1H), 3.81 (s, 2H), 2.80 (m, 1H), 1.10 (d, 6H); MS ES427 (M+H)⁺, calcd 427, RT=2.59 min; TLC (MeOH) R_(f)=0.38.

By using the method described for Example 44, and by substitutingappropriate starting materials, Examples 110-111 were similarlyprepared.

Example 45 Preparation of4-[4-(2-Amino-6-phenylpyrimidin-4-ylamino)phenoxy]pyridine-2-carboxylicacid (2-hydroxyethyl)amide

Chloropyrimidine 1A (0.2 g, 0.97 mmol) and Intermediate 2N (0.38 g, 0.97mmol), were suspended in n-butanol (5 mL) and heated at 80° C. for 12 h.LC-MS indicated that the reaction was complete. KF was then added to thereaction mixture and heating was continued at 80° C. for 5 h. Thesolvent was removed by rotary evaporation, and the residue was treatedwith 10% sodium carbonate and extracted with EtOAc (20 mL×3). Theorganic extracts were combined, washed with water and brine, dried overmagnesium sulfate, and evaporated to afford a solid that was washed withmethanol to give pure product, 0.19 g (44%). ¹H NMR (DMSO-d₆) δ 9.36 (s,1H), 8.62 (t, 1H), 8.45 (d, 1H), 7.88 (m, 4H), 7.47 (m, 3H), 7.38 (d,1H), 7.11 (m, 3H), 6.45 (s, 1H), 6.34 (s, 2H), 3.49 (t, 2H), 3.36 (t,2H); MS ES 443 (M+H)⁺ calcd 443.

Example 46 Preparation of6-phenyl-N⁴-{4-[2-(1H-tetrazol-5-yl)pyridin-4-yloxy]phenyl}pyrimidine-2,4-diamine

A mixture of4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carbonitrile(0.20 g, 0.53 mmol, prepared in Example 8), sodium azide (0.051 g, 0.79mmol), and triethylamine (0.11 g, 0.79 mmol) in toluene (15 mL) washeated at 100° C. for 2 days. The mixture was then treated with coldwater. The solid was collected by filtration, washed with water andmethanol to give pure product, 0.14 g (63%). ¹H NMR (DMSO-d₆) δ 9.51 (s,1H), 8.62 (d, 1H), 7.94 (m, 4H), 7.55 (d, 1H), 7.48 (m, 3H), 7.19 (m,3H), 6.48 (m, 3H); MS ES 424 (M+H)⁺calc 424.

Example 47 Preparation ofN⁴-{4-[2-(4,5-Dihydro-1H-imidazol-2-yl)pyridin-4-yloxy]phenyl}-6-phenylpyrimidine-2,4-diamine

A mixture of4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carbonitrile(0.2 g, 0.53 mmol, prepared in Example 8), ethylene diamine (0.095 g,1.58 mmol), and sulfur (0.05 g, 1.58 mmol) in DMF (3 mL) was heated at80° C. for 3 days. The solvent was then removed by evaporation underreduced pressure. The residue was purified by preparative HPLC followedby preparative TLC (EtOAc:NH₄OH=99:2) to afford pure product, 0.01 g(5%). ¹H NMR (DMSO-d₆) δ 9.39 (s, 1H), 8.41 (d, 1H), 7.84 (m, 4H), 7.42(m, 3H), 7.37 (d, 1H), 7.09 (m, 3H), 6.95 (s, 1H), 6.46 (s, 1H), 6.37(s, 21-1); MS ES 424 (M+H)⁺calc 424.

Example 48 Preparation ofN⁴-[4-(2-Chloro-pyridin-4-yloxy)-phenyl]-6-phenyl-pyrimidine-2,4-diamine

This compound was prepared by reaction of 1A with 2R by the methoddescribed in Example 1. ¹H NMR (DMSO-d₆) δ 9.40 (s, 1H), 8.22 (d, 1H),7.85 (m, 4H), 7.45 (m, 3H), 7.11 (m, 2H), 6.88 (m, 2H), 6.46 (s, 1H),6.36 (s, 2H); MS ES 390 (M+H)⁺, calcd 390, RT=2.27 min.

By using the method described for Example 48, and by substitutingappropriate starting materials, Examples 113-118 were similarlyprepared.

Example 49 Preparation of(S)—N⁴-{4-[2-(2-Methoxymethylpyrrolidin-1-yl)pyridin-4-yloxy]phenyl}-6-phenylpyrimidine-2,4-diamine

A mixture ofN⁴-{4-[(2-chloropyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine(0.15 g, 0.38 mmol, prepared in Example 48) and(S)-(+)-2-(methoxymethyl)pyrrolidine (2 mL) was heated at 80° C. for 3days. The mixture was cooled to rt and separated by preparative HPLCdirectly. The desired fractions were combined, neutralized by 10% sodiumcarbonate, and extracted with EtOAc (3×). The extracts were combined,dried over magnesium sulfate, and evaporated to furnish pure product,0.04 g (22%). ¹H NMR (DMSO-d₆) δ 9.24 (s, 1H), 7.89 (m, 3H), 7.78 (m,2H), 7.42 (m, 3H), 7.00 (m, 2H), 6.44 (s, 1H), 6.34 (s, 2H), 6.10 (m,1H), 5.85 (d, 1H), 4.06 (m, 2H), 3.40 (m, 1H), 3.21 (s, 3H), 3.08 (m,4H), 1.82 (m, 4H); MS ES 469 (M+H)⁺ calc 469.

By using the method described for Example 49, and by substitutingappropriate starting materials, Examples 119-147 were similarlyprepared.

Example 50 Preparation of2-amino-N-(4-{2-amino-6-[4-(2-trifluoromethylpyridin-4-yloxy)phenylamino]pyrimidin-4-yl}phenyl)-3-hydroxypropionamide

To a solution of (4S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-1 carboxylicacid (0.56 g, 2.3 mmol) in dry N,N-dimethylacetamide (10 mL) was addedHATU (0.11 g, 2.87 mmol) and DIEA (0.742 g, 5.75 mmol). After thereaction solution was stirred at rt for 1 h,6-(4-aminophenyl)-N⁴-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine (Example 165, 0.84 g,1.92 mmol) was added. The solution was stirred for an additional 24 h atrt and separated by preparative HPLC to afford a solid intermediate,which was treated with methanol (10 mL) and concentrated HCl (0.5 mL)for 12 h at rt. The resulting mixture was diluted with DMSO and purifiedby HPLC to give a solid. The solid was stirred with saturated sodiumbicarbonate and EtOAc for 2 h. The organic layer was separated, washedwith water and brine, dried over magnesium sulfate, and evaporated toafford 0.433 g (43%) of pure product. ¹H NMR (DMSO-d₆) δ 9.34 (s, 1H),8.59 (d, 1H), 7.88 (m, 4H), 7.76 (d, 2H), 7.37 (s, 1H), 7.16 (m, 3H),6.45 (s, 1H), 6.36 (s, 2H), 4.88 (t, 1H), 3.56 (m, 2H), 3.39 (m, 1H); MSES 526 (M+H)⁺calcd 526.

By using the method described for Example 50, and by substitutingappropriate starting materials, Examples 148-152 were similarlyprepared.

Example 51 Preparation of4-{2-amino-6-[(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}phenol

Step 1: Preparation of6-chloro-N⁴-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine

A stirred solution containing 2-amino-4,6-dichloropyrimidine (17.74 g,0.11 mol) and 4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}aniline(Intermediate 2U) in water (400 mL), isopropanol (100 mL) andconcentrated hydrochloric acid (5 mL) was heated at 65° C. for 18 h. Thereaction was cooled to 0° C. and the yellow-tan solid was collected bysuction filtration and washed with water. The filtered product wasdissolved in hot N,N-dimethylformamide (90° C.) and triethylamine wasslowly added until the solution was slightly basic (pH˜8). The solutionwas then cooled to rt, added to vigorously stirred ice water (1.2 L),and stirring was continued for 1 h. The tan solids were collected bysuction filtration and washed sequentially with water, isopropanol,diethyl ether and finally hexane. The material was dried by air suctionto afford a light tan solid, 28.8 g (77%). ¹H NMR (DMSO-d₆) δ ppm 9.46(s, 1H), 8.59 (d, 1H, J=5.6 Hz), 7.81 (d, 2H, J=9.0), 7.37 (d, 1H, J=2.4Hz), 7.17 (d, 2H, J=9.0 Hz), 7.11 (dd, 1H, J=2.6, 5.6 Hz), 6.78 (s, 2H),6.00 (s, 1H). MS ES 382 (M+H)⁺, calcd 382 RT=2.93 min.

Step 2: Preparation of the Title Compound

To a 8 mL microwave tube was added6-chloro-N⁴-(4-{[2-(trifluoromethyl)-pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine(0.2 g, 0.52 mmol), boronic ester (0.17 g, 0.79 mmol), PdCl₂dppf-CH₂Cl₂complex (0.023 g, 0.03 mmol), potassium carbonate (0.18 g, 1.3 mmol),N,N-dimethylacetamide (3 mL), and water (1 mL). The mixture wasdegassed, flushed with nitrogen, and heated at 150° C. for 15 min in amicrowave reactor. The mixture was filtered, and the filtrate wasseparated by prep HPLC. The desired fractions were combined, basified,and extracted with EtOAc (3×). The EtOAc extracts were then washed withwater and brine, dried over magnesium sulfate, and evaporated to give 45mg (20%) pure product. ¹H NMR (DMSO-d₆) δ 9.75 (s, 1H), 9.22 (s, 1H),8.58 (d, 1H), 7.86 (d, 2H), 7.76 (d, 2H), 7.35 (s, 1H), 7.12 (m, 3H),6.78 (m, 2H), 6.39 (s, 1H), 6.20 (s, 2H); MS ES 440 (M+H)⁺, calcd 440.

By using the method described for Example 51, and by substitutingappropriate starting materials, Examples 153-184 were similarlyprepared.

Example 52 Preparation of sulfamic acid,4-{2-amino-6-[4-(2-trifluoromethylpyridin-4-yloxy)phenylamino]pyrimidin-4-yl}phenylester

To neat chlorosulfonyl isocyanate (0.166 g, 1.37 mmol) was addeddropwise formic acid (97%, 0.63 g, 1.37 mmol) while cooling in ice-waterbath. The mixture was stirred at rt until gas evolution ceased. Theresulting sulfamoyl chloride was added to a solution of4-{2-amino-6-[(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}-phenol(0.06 g, 0.14 mmol, Example 51) in dry N,N-dimethylacetamide at 0° C.The reaction mixture was then stirred at rt for 12 h. The solution wasdiluted with methanol and separated by preparative HPLC. The desiredfractions were combined, basified with saturated sodium carbonate, andextracted with EtOAc (3×). The extracts were combined, washed withbrine, dried over magnesium sulfate, and evaporated to give desiredproduct, 0.025 g (35%). ¹H NMR (DMSO-d₆) δ 9.42 (s, 1H), 8.59 (d, 1H),8.09 (d, 2H), 7.98 (m, 2H), 7.85 (m, 2H), 7.35 (m, 3H), 7.10 (m, 3H),6.42 (s, 1H), 6.36 (s, 2H); MS ES 519 (M+H)⁺calcd 519.

By using the method described for Example 52, and by substitutingappropriate starting materials, Examples 185-186 and 332 were similarlyprepared. In addition, by selection of the appropriate startingmaterials, this method can be used for the preparation of Examples326-331, and 333-334

Example 53 Preparation ofN⁴-[4-(2-aminopyridin-4-yloxy)phenyl]-6-phenylpyrimidine-2,4-diamine

To a 8-mL vial was added Pd₂(dba)₃ (0.028 g, 0.03 mmol),2-dicyclohexylphosphinobiphenyl (0.025 g, 0.070 mmol), andN⁴-{4-[(2-chloropyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine(0.20 g, 0.51 mmol, Example 48). The vial was sealed, evacuated, andback filled with nitrogen. THF was then added via syringe, followed byaddition of LiHMDS (1M in THF, 0.72 mL, 0.72 mmol). The mixture washeated at 65° C. overnight. The mixture was then cooled to rt, treatedwith 1N HCl, and stirred for 12 h at rt. The mixture was thenneutralized using 1N NaOH and extracted with methylene chloride (10mL×3). The organic extracts were combined, washed with brine, dried overmagnesium sulfate, and purified by preparative HPLC to furnish 0.035 gof the desired product (18%). ¹H NMR (CD₃OD) δ 7.96 (d, 2H), 7.79 (m,3H), 7.60 (m, 3H), 7.22 (m, 2H), 6.61 (d, 1H), 6.58 (s, 1H), 6.20 (s,1H); MS ES 371 (M+H)⁺ calcd 371.

Example 54 High-Speed Analoging (HSA) Synthesis Method A

To a mixture of 1 equivalent of the chloropyrimidine (100 mg, e.g.compound 9 General Method B), 2 equivalent of boronic acid (e.g. GeneralMethod B), and 0.06 equivalent of PdCl₂(dppf) CH₂Cl₂ complex in 2.3 mLanhydrous N,N-dimethylacetamide in a 5 mL, microwave reaction vessel wasadded 3.1 equivalent of 2 M K₂CO₃ aqueous solution. After the resultingmixture was degassed for 10 min using N₂, the vial was sealed and heatedat 150° C. for 20 min in a microwave reactor. The reaction mixture wasfiltered, and the filtrate was purified by pre-HPLC eluting with 15% to85% acetonitrile using a Phenomenex Luna 5μ C18 150×30 mm column toprovide the final product.

By using the appropriate starting materials, the method described forExample 54, was utilized for the preparation of Examples 112 and187-219.

Example 55 High-Speed Analoging (HSA) Synthesis Method B

To a mixture of 1 equivalent of the chloropyrimidine (100 mg, e.g.compound 9 General Method B), 2 equivalents of boronic acid (GeneralMethod B), and 0.06 equivalent of PdCl₂(dppf) CH₂Cl₂ complex in 2.3 mLanhydrous N,N-dimethylacetamide in a 8 mL microwave reaction vessel wasadded 3.1 equivalent of 2M K₂CO₃ aqueous solution. After the resultingmixture was degassed for 10 min using N₂, the vial was sealed and heatedat 140° C. for 20 min in a microwave reactor. The reaction mixture wasfiltered, and the filtrate was purified by pre-HPLC eluting with 15% to85% acetonitrile using a Phenomenex Luna 5μ C18 150×30 mm column toprovide the final product.

By using the appropriate starting materials, the method described forExample 55, was utilized for the preparation of Examples 220-279

Example 56 High-Speed Analoging (HSA) Synthesis Method C

A mixture of 1 equivalent chloropyrimidine (e.g. compound 9 GeneralMethod B), 2 equivalents of boronic acid (General Method B), and 0.1equivalent of PdCl₂(dppf)-CH₂Cl₂ complex in 2.5 mL anhydrousN,N-dimethylacetamide and 0.5 mL of 2 M K₂CO₃ in water in a 5 mLmicrowave reaction vessel under nitrogen was heated at 140° C. for 20min in the personal microwave reactor. The reaction mixture wasfiltered, and the filtrate was purified by pre-HPLC eluting with 15% to85% acetonitrile containing 0.1% TFA using a Phenomenex Luna 5μ C18150×30 mm column to provide the final product.

By using the appropriate starting materials, the method described forExample 56, was utilized for the preparation of Examples 280-325

Example 57 Preparation of4-[2-amino-6-({4-[(2-chloropyridin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]phenol

Step 1: Preparation of 4-(2-amino-6-chloropyrimidin-4-yl)phenyltert-butyl

To a mixture of 2-amino-4,6-dichloropyrimidine (1.5 g, 9.15 mmol),t-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl carbonate(2.9 g, 9.15 mmol), PdCl₂dppf CH₂Cl₂ complex (0.45 g, 0.55 mmol), andDME (14 mL) was added a solution of potassium carbonate (3.2 g, 22.9mmol) in water (4 mL). The mixture was then degassed, flushed withnitrogen and heated at 80° C. overnight. The organic layer wasseparated, washed with water and brine, dried over magnesium sulfate,and evaporated. The residue was purified by column (2% MeOH:50%hexane:48% EtOAc) to afford 0.64 g (22%) desired product. MS ES 322(M+H)⁺, calcd 322, RT=3.37 min.

Step 2: Preparation of Title Compound

This material was prepared by a method analogous to that described forExample 1, starting from the product from4-(2-amino-6-chloropyrimidin-4-yl)phenyl tert-butyl carbonate andIntermediate 2R. ¹H NMR (DMSO-d₆) δ 9.79 (s, 1H), 9.25 (s, 1H), 8.22 (d,1H), 7.86 (m, 2H), 7.74 (m, 2H), 7.09 (m, 2H), 6.95 (m, 2H), 6.80 (m,2H), 6.39 (s, 1H), 6.23 (s, 2H); MS ES 406 (M+H)⁺, calcd 406, RT=2.74min.

Example 58 Preparation of(3E)-4-(4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)but-3-en-1-ol

N⁴-{4-[(2-chloropyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine(0.10 g, 0.26 mmol, Example 48), K₂CO₃ (0.089 g, 0.64 mmol), and DMA(2.5 mL) were placed into a small microwave vial. The mixture wasdegassed for 10 min before(3E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-ol (0.10g, 0.33 mmol) and Pd(dppf)Cl₂ CH₂Cl₂ complex (0.012 g, 0.020 mmol) wereadded. The mixture was heated at 150° C. for 20 min in a microwavereactor. The mixture was cooled, filtered, and purified by prep-HPLC.Concentration of the desired fractions gave 0.016 g of the titlecompound (10%). MS ES: 426 (M+H)⁺, calcd 426, RT=1.90 min.

Example 59 Preparation of(4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methanoltrifluoroacetate)

To a cloudy solution of4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxylicacid (748 mg, 1.87 mmol, Example 20) in anhydrous DMF (50 mL) at rt wasadded carbonyldiimidazole (456 mg, 2.81 mmol). The white suspension wasstirred at 80° C. overnight, concentrated to a volume of 10 mL, anddiluted with anhydrous THF (7 mL). The reaction mixture was cooled to 0°C. and water (10 mL) was added. The mixture was vigorously stirred asNaBH₄ (142 mg, 3.75 mmol) was added and was allowed to warm from 0° C.to rt over 2 h before it was quenched with conc. HCl (1 mL) in an icebath. After stirring for 15 min, the mixture was slowly added to astirred solution of sat. NaHCO₃ (20 mL) at 0° C. After stirring for 30min, it was extracted with EtOAc (3×100 mL). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated to give an off-whitegum (420 mg, 85% pure). The crude material (100 mg) was purified by prepHPLC purification to give 37 mg (40% yield) of the title compound as acolorless gum. ¹H NMR (DMSO-d₆) δ 10.8 (s, 1H), 8.55 (d, 1H), 7.90 (m,2H), 7.75 (m, 2H), 7.60 (m, 3H), 7.35 (d, 2H), 7.20 (m, 2H), 6.60 (s,1H), 4.60 (s, 2H); MS ES 386 (M+H)⁺calcd 386, RT=1.73 min.

Examples of the compounds of the invention are summarized in Table 1below. It is to be noted that in some of the IUPAC names, “N4*” is to beunderstood as a symbol for “N⁴”.

TABLE 1 Exam- LCMS: ple [M + H]⁺ No. Structure IUPAC Name* (RT, min) 1

N⁴-{4-[(2-ethylpyridin-4-yl) oxy]phenyl}-6-phenylpyrimidine- 2,4-diamine384 (1.87) 2

N⁴-{4-[(2-methylpyridin-4-yl) oxy]phenyl}-6-phenylpyrimidine-2,4-diamine 370 (1.41) 3

4-{3-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxamide 399.4 (2.74) 4

4-{3-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}-N-methylpyridine-2-carboxamide 413 (2.13) 5

N⁴-{4-[(3,5-difluoropyridin-4-yl) oxy]phenyl}-6-phenyl-pyrimidine-2,4-diamine 392 (2.27) 6

4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]-3-fluorophenoxy}pyridine-2- carbonitrile hydrochloride 399.3 (2.06) 7

N4*-{3-fluoro-4-[(2- methylpyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine 388 (1.70) 8

4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridine-2-carbonitrile 381 (2.22) 9

4-(3-{[2-amino-6-(3-furyl) pyrimidin-4-yl]amino}phenoxy)-N-methylpyridine-2-carboxamide 403 (1.99) 10

4-(4-{[2-amino-6-(3-furyl) pyrimidin-4-yl]amino}phenoxy)-N-methylpyridine-2-carboxamide 403 (1.94) 11

N4*-[4-(4-nitrophenoxy)phenyl]- 6-phenylpyrimidine-2,4-diamine 400(3.01) 12

N4*-[4-(4-chlorophenoxy)phenyl]- 6-phenylpyrimidine-2,4-diamine 389(2.78) 13

N4*-[4-(4-methoxyphenoxy) phenyl]-6-phenylpyrimidine-2,4- diamine 385(2.48) 14

4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]-2-fluorophenoxy}pyridine-2- carbonitrile 15

4-[4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]-3-(trifluoromethyl)phenoxy] pyridine-2-carbonitrile 16

N⁴-{4-[(2-methylpyrimidin-4-yl) oxy]phenyl}-6-phenylpyrimidine-2,4-diamine 17

N⁴-{4-[(2-methylpyridin-4-yl) oxy]phenyl}-6-[4-(2-pyrrolidin-1-ylethoxy)phenyl]pyrimidine- 2,4-diamine 18

4-[4-({2-amino-6-[4-(2-piperidin- 1-ylethoxy)phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2- carbonitrile 19

methyl 4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxylate 414.2 (2.16) 20

4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxylic acid 400 (1.71) 21

N4*-(4-{[2-(morpholin-4- ylcarbonyl)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4- diamine trifluoroacetate 469.2 (2.13) 22

4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}-N,N-dimethylpyridine-2- carboxamide 23

4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}-N-(2-methoxyethyl)pyridine-2- carboxamide 457.4 (2.17) 24

4-[4-({2-amino-6-[4-(trifluoro- methyl)phenyl]pyrimidin-4-yl}amino)phenoxy]-N-(2-methoxy- ethyl)pyridine-2-carboxamide 25

4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]benzyl}-N-(2-methoxyethyl)-N- methylpyridine-2-carboxamide 26

N4*-[4-({2-[(4-methylpiperazin- 1-yl)carbonyl]pyridin-4-yl}oxy)phenyl]-6-phenylpyrimidine-2,4- diamine trifluoroacetate 482.2 (1.86) 27

N⁴-{4-[(2-{[(2-methoxyethyl) amino]methyl}pyridin-4-yl)oxy]phenyl}6-phenylpyrimidine-2,4- diamine 28

6-(4-fluorophenyl)-N⁴-(4-{[2- (piperidin-1-ylmethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 29

6-(4-methoxyphenyl)-N⁴-(4-{[2- (morpholin-4-ylmethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 30

N²-ethyl-6-(3-methoxyphenyl)- N4*-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl) pyrimidine-2,4-diamine trifluoroacetate 482(2.83) 31

4-{4-[(2-amino-5-bromo-6- phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carbonitrile 459.3 (2.85) 32

N4*-(4-{[2-(2-morpholin-4- ylethoxy)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4- diamine 485.1 (1.96) 33

6-phenyl-N⁴-(4-{[2-(trifluoro- methyl)pyridin-4-yl]methyl}phenyl)pyrimidine-2,4-diamine 422.3 (2.51) 34

N4*-{4-[(2-chloropyridin-4-yl) methyl]phenyl}-6-phenyl-pyrimidine-2,4-diamine 388.3 (2.38) 35

4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]benzyl}pyridine-2-carbonitrile 379.3 (2.35) 36

N4*-(4-{[2-(aminomethyl) pyridin-4-yl]methyl}phenyl)-6-phenylpyrimidine-2,4-diamine 383.3 (1.84) 37

6-phenyl-N4*-(4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 424.3 (2.48) 38

N4*-(4-{[1-oxido-2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine 440.3 (2.97) 39

N4*-(4-{[2-(aminomethyl)pyridin- 4-yl]oxy}phenyl)-6-phenyl-pyrimidine-2,4-diamine 385.2 (1.80) 40

N-[(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl] methanesulfonamide trifluoroacetate 463.3 (1.17) 41

N-[(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl]-4- fluorobenzamide 507.7 (2.5)  42

N′-[(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}-pyridin-2-yl)methyl]-N,N- diethylurea 484.4 (2.37) 43

N4*-[4-({4-[2-(methoxymethyl) pyrrolidin-1-yl]pyridin-2-yl}oxy)phenyl]-6-phenylpyrimidine-2,4- diamine 469.4 (1.90) 44

N4*-[4-({2-[(isopropylamino) methyl]pyridin-4-yl}oxy)phenyl]-6-phenylpyrimidine-2,4-diamine 427.1 (2.59) 45

4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}-N-(2-hydroxyethyl)pyridine-2- carboxamide 443.3 (2.19) 46

6-phenyl-N4*-(4-{[2-(1H-tetrazol- 5-yl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 424.1 (1.84) 47

N4*-(4-{[2-(4,5-dihydro-1H- imidazol-2-yl)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4- diamine 424.2 (0.81) 48

N4*-{4-[(2-chloropyridin-4-yl) oxy]phenyl}-6-phenylpyrimidine-2,4-diamine 390.3 (2.40) 49

N4*-[4-({2-[(2S)-2-(methoxy- methyl)pyrrolidin-1-yl]pyridin-4-yl}oxy)phenyl]-6-phenyl- pyrimidine-2,4-diamine 469.3 (1.36) 50

N-(4-{2-amino-6-[(4-{[2-(tri- fluoromethyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl} phenyl)serinamide 536.1 (2.14) 51

4-{2-amino-6-[(4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}phenol 440.3 (1.56) 52

4-{2-amino-6-[(4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}phenyl sulfamate 519.1 (2.64) 53

N4*-{4-[(2-aminopyridin-4-yl) oxy]phenyl}-6-phenylpyrimidine-2,4-diamine 371.4 (1.90) 57

4-[2-amino-6-({4-[(2-chloro- pyridin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]phenol 406.4 (2.74) 58

(3E)-4-(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)but-3-en-1-ol trifluoroacetate (salt) 426.3 (1.90) 59

(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methanol trifluoroacetate 386.2 (1.73) 60

ethyl 2-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]-5-[(5-chloropyridin-3-yl)oxy]benzoate 462.2 (2.53) 61

6-phenyl-N4*-[4-(pyrimidin-5- yloxy)phenyl]pyrimidine-2,4- diamine 357.3(2.07) 62

N⁴-[4-(4-aminophenoxy)phenyl]- 6-phenylpyrimidine-2,4-diamine 370.3(2.08) 63

N4*-{4-[(4-bromopyridin-2-yl) oxy]phenyl}-6-phenylpyrimidine-2,4-diamine 436.1 (2.81) 64

N4*-{4-[(2-fluoropyridin-4-yl) oxy]phenyl}-6-phenylpyrimidine-2,4-diamine trifluoroacetate 374.7 (2.52) 65

4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy} pyridin-2-ol372.9 (2.34) 66

N4*-{4-[(2-chloropyridin-4-yl) oxy]-2-fluorophenyl}-6-phenyl-pyrimidine-2,4-diamine 408.3 (1.42) 67

N4*-(2-fluoro-4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine 442.3 (2.54) 68

4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy} benzonitrile380.4 (2.39) 69

4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxamide 399.3 (2.54) 70

4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}-N-methylpyridine-2-carboxamide 413.3 (2.21) 71

4-(4-{[2-amino-6-(4-fluorophenyl) pyrimidin-4-yl]amino}phenoxy)-N-methylpyridine-2-carboxamide 431.3 (2.25) 72

4-(3-{[2-amino-6-(4-fluorophenyl) pyrimidin-4-yl]amino}phenoxy)-N-methylpyridine-2-carboxamide 431.5 (2.15) 73

4-(4-{[2-amino-6-(4-fluorophenyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 417.3 (2.07) 74

4-(3-{[2-amino-6-(4-fluorophenyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 417.3 (2.09) 75

4-(4-{[2-amino-6-(4-fluorophenyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 399.4 (2.21) 76

4-(3-{[2-amino-6-(3-methoxy- phenyl)pyrimidin-4-yl]amino}phenoxy)-N-methylpyridine-2- carboxamide 443.4 (2.18) 77

4-(3-{[2-amino-6-(4-methoxy- phenyl)pyrimidin-4-yl]amino}phenoxy)-N-methylpyridine-2- carboxamide 443.4 (2.19) 78

4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxylic acid hydrochloride 400.1 (1.67) 79

4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}-N-1-azabicyclo[2.2.2]oct-3- ylpyridine-2-carboxamide trifluoroacetate508.3 (1.99) 80

4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}-N-(2,3-dihydroxypropyl)pyridine- 2-carboxamide 473.2 (2.11) 81

N4*-{4-[(2-{[(2S)-2-(methoxy- methyl)pyrrolidin-1-yl]carbonyl}pyridin-4-yl)oxy]phenyl}-6- phenylpyrimidine-2,4-diaminetrifluoroacetate 497.3 (2.23) 82

(3R)-1-[(4-{4-[(2-amino-6- phenylpyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)carbonyl] pyrrolidin-3-ol trifluoroacetate (salt)469.4 (1.98) 83

N4*-{4-[(2-butoxypyridin-4-yl) oxy]phenyl}-6-phenylpyrimidine-2,4-diamine 428.3 (2.56) 84

N⁴-(4-{[2-(2-methoxyethoxy) pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine 430.3 (2.24) 85

N⁴-[4-({2-[2-(dimethylamino) ethoxy]pyridin-4-yl}oxy) phenyl]-6-phenylpyrimidine-2,4-diamine 443.1 (1.94) 86

N4*-{4-[(2-ethoxypyridin-4-yl) oxy}phenyl}-6-phenylpyrimidine-2,4-diamine 400.3 (2.24) 87

1-[4-({5-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]pyridin-2-yl}oxy)phenyl]ethanone 398.2 (2.29) 88

N^(4*)-[4-(4-aminobenzyl)phenyl]- 6-phenylpyrimidine-2,4-diamine 368.3(1.91) 89

N⁴-[4-(4-methylbenzyl)phenyl]-6- phenylpyrimidine-2,4-diamine 367.4(2.78) 90

N⁴-[4-(4-methoxybenzyl)phenyl]- 6-phenylpyrimidine-2,4-diamine 398.2(2.29) 91

N⁴-[4-(4-fluorobenzyl)phenyl]-6- phenylpyrimidine-2,4-diamine 371.4(2.68) 92

N4*-(4-{[2-(aminomethyl)pyridin- 4-yl]oxy}phenyl)-6-phenyl-pyrimidine-2,4-diamine trifluoroacetate 385.2 (1.86) 93

N-[(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl]-1-methyl- 1H-imidazole-4-sulfonamidetrifluoroacetate 529.3 (1.15) 94

N-[(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl] ethanesulfonamide trifluoroacetate 477.4 (1.89) 95

N-[(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl]propane-2- sulfonamide trifluoroacetate 491.4 (2.06)96

N-[(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl]benzene- sulfonamide trifluoroacetate 525.4 (2.20)97

N-[(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl]-4-methoxy- benzenesulfonamide trifluoroacetate555.4 (2.21) 98

N-[(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy)pyridin-2-yl)methyl]-4-fluoro- benzenesulfonamide trifluoroacetate 543.4(2.24) 99

N′-[(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl]-N,N- dimethylurea 457.1 (2.52) 100

N-[(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl]morpholine- 4-carboxamide 498.4 (2.37) 101

N-[(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl]urea trifluoroacetate 428.3 (0.72) 102

N-[(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl]-N,N′,N′- trimethylurea 470.1 (1.88) 103

N-[(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl]-N′,N′-diethyl- N-methylurea 498.2 (2.04) 104

N-[(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl]-N-methyl- morpholine-4-carboxamide 512.2 (1.88) 105

N4*-{4-[(4-morpholin-4- ylpyridin-2-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine 441.4 (1.27) 106

6-phenyl-N4*-{4-[(4-piperidin-1- ylpyridin-2-yl)oxy]phenyl}pyrimidine-2,4-diamine 439.4 (1.93) 107

N4*-(4-{[4-(4-methylpiperazin-1- yl)pyridin-2-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine 454.2 (2.22) 108

2,2′-[(2-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-4-yl)imino]diethanol 459.3 (2.38) 109

N4*-[4-({4-[bis(2-methoxyethyl) amino]pyridin-2-yl}oxy)phenyl]-6-phenylpyrimidine-2,4-diamine 488.0 (2.32) 110

N4*-{4-[(2-{[(1-ethylpropyl) amino]methyl}pyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine- 2,4-diamine 455.2 (2.47) 111

N4*-[4-({2-[(cyclohexylamino) methyl]pyridin-4-yl}oxy)phenyl]-6-phenylpyrimidine-2,4-diamine 467.1 (2.42) 112

6-(3,4-dichlorophenyl)-N4*-(4- {[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 492.3 (3.29) 113

N4*-{3-[(2-chloropyridin-4-yl) oxy]phenyl}-6-phenylpyrimidine-2,4-diamine 390.3 (2.37) 114

N4*-{4-[(2-chloropyridin-4-yl) oxy}phenyl}-6-(4-fluorophenyl)pyrimidine-2,4-diamine 408.3 (1.04) 115

N4*-{4-[(2-chloropyridin-4-yl) oxy]phenyl}-6-(3-nitrophenyl)pyrimidine-2,4-diamine 435.2 (1.27) 116

6-(4-aminophenyl)-N4*-{4-[(2- chloropyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 405.3 (1.60) 117

N4*-{4-[(2-chloropyridin-4-yl) oxy]-3-fluorophenyl}-6-phenyl-pyrimidine-2,4-diamine 408.2 (1.72) 118

6-(3-aminophenyl)-N4*-{4-[(2- chloropyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 405.3 (1.05) 119

6-phenyl-N4*-{3-[(2-piperidin-1- ylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 439.3 (0.25) 120

N4*-{3-[(2-morpholin-4- ylpyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine 441.3 (0.25) 121

6-phenyl-N4*-{3-[(2-pyrrolidin-1- ylpyridin-4-yl)oxy]phenyl}pyridine-2,4-diamine 425.3 (0.25) 122

N4*-[3-({2-[2-(methoxymethyl) pyrrolidin-1-yl]pyridin-4-yl}oxy)phenyl]-6-phenylpyrimidine- 2,4-diamine 469.3 (0.21) 123

[(2R)-1-(4-{3-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)pyrrolidin-2-yl] methanol 455.4 (2.34) 124

N4*-[3-({2-[(2-methoxyethyl) (methyl)amino]pyridin-4-yl}oxy)phenyl]-6-phenylpyrimidine- 2,4-diamine 443.4 (1.71) 125

N4*-(3-{[2-(2-methylpyrrolidin-1- yl)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine 439.3 (2.01) 126

N4*-[3-({2-[bis(2-methoxyethyl) amino]pyridin-4-yl}oxy)phenyl]-6-phenylpyrimidine-2,4-diamine 487.2 (1.03) 127

2,2′-[(4-{3-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)imino]diethanol 459.3 (0.93) 128

[(2S)-1-(4-{3-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)pyrrolidin-2-yl] methanol 455.4 (2.41) 129

2,2′-[(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)imino]diethanol 459.4 (2.34) 130

N4*-(3-{[2-(4-methylpiperazin-1- yl)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine 454.3 (2.37) 131

N4*-(4-{[2-(1-benzylhydrazino) pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine 476.2 (2.19) 132

N4*-(4-{[2-(benzylamino)pyridin- 4-yl]oxy}phenyl)-6-phenyl-pyrimidine-2,4-diamine trifluoroacetate 461.3 (2.10) 133

N4*-[4-({2-[(2R)-2-(methoxy- methyl)pyrrolidin-1-yl]pyridin-4-yl}oxy)phenyl]-6-phenyl- pyrimidine-2,4-diamine 469.3 (0.96) 134

N4*-{4-[(2-morpholin-4- ylpyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine 441.3 (1.74) 135

N4*-(4-{[2-(4-methylpiperazin-1- yl)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine 454.2 (1.47) 136

N4*-[4-({2-[4-(2-methoxyethyl) piperazin-1-yl]pyridin-4-yl}oxy)phenyl]-6-phenylpyrimidine-2,4- diamine 498.2 (1.59) 137

N4*-[4-({2-[(2-methoxyethyl) (methyl)amino]pyridin-4-yl}oxy)phenyl]-6-phenylpyrimidine-2,4- diamine 443.3 (0.82) 138

N4*-{4-[(2-{[2-(dimethylamino) ethyl]amino}pyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4- diamine 442.2 (0.82) 139

6-phenyl-N4*-{4-[(2-piperidin-1- ylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 439.3 (1.82) 140

N4*-[4-({2-[bis(2-methoxyethyl) amino]pyridin-4-yl}oxy)phenyl]-6-phenylpyrimidine-2,4-diamine 487.2 (1.34) 141

N4*-{4-[(2-{[3-(diethylamino) propyl]amino}pyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4- diamine 484.2 (0.86) 142

N4*-[4-({2-[(3-morpholin-4- ylpropyl)amino]pyridin-4-yl}oxy)phenyl]-6-phenylpyrimidine-2,4- diamine 498.2 (0.94) 143

4-[2-amino-6-({4-[(2-morpholin- 4-ylpyridin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]-2- methoxyphenol 487.3 (0.97) 144

N4*-[4-({2-[(3S)-3-(dimethyl- amino)pyrrolidin-1-yl]pyridin-4-yl}oxy)phenyl]-6-phenyl- pyrimidine-2,4-diamine 468.2 (1.01) 145

[(2S)-1-(4-{4-[(2-amino-6- phenylpyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)pyrrolidin- 2-yl]methanol 455.3 (1.91) 146

(3R)-1-(4-{4-[(2-amino-6-phenyl- pyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)pyrrolidin-3-ol 441.3 (1.31) 147

N4*-[3-({2-[(2R)-2-(methoxy- methyl)pyrrolidin-1-yl]pyridin-4-yl}oxy)phenyl]-6-phenyl- pyrimidine-2,4-diamine 469.4 (1.71) 148

4-[(4-{2-amino-6-[(4-{[2-(tri- fluoromethyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl} phenyl)amino]-4-oxobutanoic acid 539.4(2.25) 149

4-{2-amino-6-[(4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}-2- methoxyphenyl N-(tert-butoxy-carbonyl)glycinate 627.0 (2.8)  150

4-{2-amino-6-[(4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}-2- methoxyphenyl glycinate hydrochloride 527.2(2.54) 151

N-(4-{2-amino-6-[(4-{[2-(tri- fluoromethyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl} phenyl)glycinamide trifluoroacetate 496.2(2.11) 152

4-amino-N-(4-{2-amino-6-[(4- {[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin- 4-yl}phenyl)butanamide trifluoroacetate524.1 (2.15) 153

6-(4-amino-3-methoxyphenyl)- N4*-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl) pyrimidine-2,4-diamine 469.4 (2.67) 154

N4*-(4-{[2-(aminomethyl)pyridin- 4-yl]oxy}phenyl)-6-(2-methyl-phenyl)pyrimidine-2,4-diamine 399.6 (2.15) 155

6-[2-(trifluoromethyl)phenyl]- N4*-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl) pyrimidine-2,4-diamine 493.0 (2.96) 156

6-(2-ethylphenyl)-N4*-(4-{[2-(tri- fluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 452.9 (2.89) 157

6-(2-ethoxyphenyl)-N4*-(4-{[2- (trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 469.0 (2.81) 158

6-(2-fluoro-5-methylphenyl)-N4*- (4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 456.7 (2.87) 159

6-(2,3-difluorophenyl)-N4*-(4- {[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 460.0 (2.89) 160

6-(2,5-difluorophenyl)-N4*-(4- {[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 460.7 (2.78) 161

6-[2-(trifluoromethoxy)phenyl]- N4*-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl) pyrimidine-2,4-diamine 508.6 (2.78) 162

6-(2-isopropylphenyl)-N4*-(4- {[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 466.7 (2.99) 163

N4*-(4-{[2-(aminomethyl)pyridin- 4-yl]oxy}phenyl)-6-(2-ethyl-phenyl)pyrimidine-2,4-diamine 413.3 (1.99) 164

6-(4-aminophenyl)-N4*-(4-{[2- (trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine hydrochloride 439.3 (2.47) 165

6-(4-aminophenyl)-N4*-(4-{[2- (trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 439.3 (2.37) 166

4-{2-amino-6-[(4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}-2- methoxyphenol 470.2 (1.46) 167

3-{2-amino-6-[(4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}phenol 440.3 (1.08) 168

6-(3-amino-4-methoxyphenyl)- N4*-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl) pyrimidine-2,4-diamine 469.3 (2.45) 169

6-(3-aminophenyl)-N4*-(4-{[2- (trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 439.3 (2.37) 170

6-(3-aminophenyl)-N4*-(4-{[2- (trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine hydrochloride 439.4 (2.36) 171

4-(4-{[2-amino-6-(4-hydroxy-3- methoxyphenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carbonitrile 427.3 (2.16) 172

4-(4-{[2-amino-6-(3-amino-4- methoxyphenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carbonitrile 426.3 (2.10) 173

4-(4-{[2-amino-6-(4-amino-3- methoxyphenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carboxamide 444.2 (2.22) 174

4-{2-amino-6-[(4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}-3- methylphenol 454.3 (2.48) 175

(2-{2-amino-6-[(4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}phenyl) methanol 454.2 (2.38) 176

4-{2-amino-6-[(4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}-3-(tri- fluoromethyl)phenol 508.2 (2.62) 177

6-(4-amino-3-fluorophenyl)-N4*- (4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 457.3 (2.52) 178

tert-butyl {4-[2-amino-6-({4-[(2- cyanopyridin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]-2- methoxyphenyl}carbamate 526.2 (2.79) 179

4-(4-{[2-amino-6-(4-amino-3- methoxyphenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carbonitrile trifluoroacetate 426.2 (2.31) 180

6-(4-amino-3-methylphenyl)-N4*- (4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine- 2,4-diamine 453.4 (2.26) 181

6-(6-aminopyridin-3-yl)-N4*- (4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine- 2,4-diamine 440.3 (2.01) 182

6-(3-amino-4-chlorophenyl)-N4*- (4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine- 2,4-diamine 473.3 (2.61) 183

4-(4-{[2-amino-6-(6-amino- pyridin-3-yl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carbonitrile 397.3 (1.85) 184

2-amino-5-{2-amino-6-[(4-{[2- (trifluoromethyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4- yl}benzonitrile 464.4 (2.54) 185

4-{2-amino-6-[(4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}-2- methoxyphenyl sulfamate 549.1 (2.66) 186

N-(4-{2-amino-6-[(4-{[2-(tri- fluoromethyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl} phenyl)sulfamide 518.1 (2.42) 187

6-biphenyl-4-yl-N4*-(4-{[2-(tri- fluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 499.5 (3.29) 188

6-(2-thienyl)-N4*-(4-{[2-(tri- fluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 429.4 (2.97) 189

6-(3,4-dimethoxyphenyl)-N4*- (4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 483.4 (3.03) 190

6-(4-methoxyphenyl)-N4*-(4- {[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 453.4 (3.07) 191

6-(6-methoxypyridin-3-yl)-N4*- (4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 454.4 (3.00) 192

6-(3-fluorophenyl)-N4*-(4-{[2- (trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 441.4 (3.03) 193

6-(2-fluorophenyl)-N4*-(4-{[2- (trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 441.4 (3.03) 194

6-(2-aminophenyl)-N4*-(4-{[2- (trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 438.4 (2.96) 195

6-(3-furyl)-N4*-(4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 413.4 (2.94) 196

6-(4-fluorophenyl)-N4*-(4-{[2- (trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 441.4 (3.03) 197

6-[3-(trifluoromethyl)phenyl]- N4*-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl) pyrimidine-2,4-diamine 491.4 (3.18) 198

3-{2-amino-6-[(4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}benzonitrile 448.4 (3.00) 199

6-[4-(dimethylamino)phenyl]- N4*-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl) pyrimidine-2,4-diamine 466.4 (3.11) 200

6-(3-ethylphenyl)-N4*-(4-{[2-(tri- fluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 451.4 (3.18) 201

6-(5-isopropyl-2-methoxyphenyl)- N4*-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl) pyrimidine-2,4-diamine 495.5 (3.29) 202

6-(2-methylphenyl)-N4*-(4-{[2- (trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 437.4 (3.07) 203

6-(4-methoxypyridin-3-yl)-N4*- (4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 454.4 (2.67) 204

6-(2,4-difluorophenyl)-N4*- (4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 459.3 (3.03) 205

(3-{2-amino-6-[(4-{[2-(tri- fluoromethyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl} phenyl)methanol 453.4 (2.92) 206

6-(3-methoxyphenyl)-N4*-(4-{[2- (trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 453.4 (3.07) 207

6-[4-(ethylthio)phenyl]-N4*-(4- {[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 483.5 (3.18) 208

6-(3-amino-4-methylphenyl)-N4*- (4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 452.4 (3.03) 209

6-(4-isopropylphenyl)-N4*- (4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 465.5 (3.22) 210

(4-{2-amino-6-[(4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}phenyl) acetonitrile 462.4 (3.00) 211

6-(4-methylphenyl)-N4*-(4-{[2- (trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 437.4 (3.11) 212

6-(3-methylphenyl)-N4*-(4-{[2- (trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 437.4 (3.11) 213

6-pyridin-3-yl-N4*-(4-{[2-(tri- fluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 424.4 (2.81) 214

6-(3-thienyl)-N4*-(4-{[2-(tri- fluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine 429.4 (3.00) 215

6-(2,5-dimethoxyphenyl)-N4*- (4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 483.4 (3.07) 216

6-[3-(trifluoromethoxy)phenyl]- N4*-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}pheny) pyrimidine-2,4-diamine 507.4 (3.22) 217

6-[4-(trifluoromethoxy)phenyl]- N4*-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl) pyrimidine-2,4-diamine 507.4 (3.22) 218

6-(3,5-difluorophenyl)-N4*-(4- {[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4- diamine 459.4 (3.07) 219

4-(4-{[2-amino-6-(1H-pyrrol-2- yl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile hydrochloride 370.3 (2.65) 220

4-(4-{[2-amino-6-(4-butylphenyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 437.5 (3.47) 221

4-(4-{[2-amino-6-(2-fluorobi- phenyl-4-yl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carbonitrile 475.5 (3.36) 222

4-[4-({2-amino-6-[3-(benzyloxy) phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2-carboxamide 505.1 (3.29) 223

4-(4-{[2-amino-6-(6-methoxy- pyridin-3-yl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carbonitrile 412.4 (2.92) 224

4-(4-{[2-amino-6-(3,4- dimethoxyphenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carbonitrile 441.4 (2.92) 225

4-(4-{[2-amino-6-(4-methoxy- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 4-(4-{[6-amino-2-(4-methoxy-phenyl)pyrimidin-4-yl]amino} phenoxy)pyridine-2-carbonitrile 411.4(2.96) 226

4-(4-{[2-amino-6-(3-hydroxy- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 4-(4-{[6-amino-2-(3-hydroxy-phenyl)pyrimidin-4-yl]amino} phenoxy)pyridine-2-carbonitrile 397.4(3.07) 227

4-(4-{[2-amino-6-(4-hydroxy- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 4-(4-{[6-amino-2-(4-hydroxy-phenyl)pyrimidin-4-yl]amino} phenoxy)pyridine-2-carbonitrile 397.4(2.89) 228

4-(4-{[2-amino-6-(3-furyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 4-(4-{[6- amino-2-(3-furyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carbonitrile 371.4 (2.89) 229

4-(4-{[2-amino-6-(4-aminophenyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 4-(4-{[6- amino-2-(4-aminophenyl)pyrimidin-4-yl]amino}phenoxy) pyridine-2-carbonitrile 396.4 (2.89) 230

4-(4-{[2-amino-6-(6-methoxy- pyridin-3-yl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carboxamide 430.4 (2.74) 231

4-[4-({2-amino-6-[4-(methylthio) phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2-carbonitrile 427.5 (3.00) 232

4-[4-({2-amino-6-[4-(dimethyl- amino)phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2- carbonitrile 424.4 (3.00) 233

4-(4-{[2-amino-6-(2,5- dimethoxyphenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carbonitrile 441.4 (3.00) 234

4-(4-{[2-amino-6-(3-methoxy- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 411.4 (2.92) 235

4-[4-({2-amino-6-[4- (cyanomethyl)phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2- carbonitrile 420.4 (2.89) 236

4-{4-[(2-amino-6-pyridin-3-yl- pyrimidin-4-yl)amino]phenoxy}pyridine-2-carbonitrile 382.4 (2.78) 237

4-{4-[(2-amino-2′,4′-dimethoxy- 4,5′-bipyrimidin-6-yl)amino]phenoxy}pyridine-2-carbonitrile 443.4 (2.85) 238

4-(4-{[2-amino-6-(3-aminophenyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 396.4 (3.00) 239

4-(4-{[2-amino-6-(2-thienyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 387.4 (3.07) 240

4-(4-{[2-amino-6-(3-fluoro- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 399.4 (3.14) 241

4-(4-{[2-amino-6-(2-fluoro- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 399.4 (3.14) 242

4-(4-{[2-amino-6-(4-chlorophenyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 415.8 (3.14) 243

4-(4-{[2-amino-6-(2-aminophenyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 396.4 (3.11) 244

4-[4-({2-amino-6-[3-(trifluoro- methyl)phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2- carbonitrile 449.4 (3.29) 245

4-(4-{[2-amino-6-(5-isopropyl-2- methoxyphenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carbonitrile 453.5 (3.36) 246

4-(4-{[2-amino-6-(2-methyl- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 395.4 (3.14) 247

4-(4-{[2-amino-6-(2,4-difluoro- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 417.4 (3.11) 248

4-[4-({2-amino-6-[3-(hydroxy- methyl)phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2- carbonitrile 411.4 (3.03) 249

4-(4-{[2-amino-6-(4-methyl- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 395.4 (3.18) 250

4-(4-{[2-amino-6-(3-methyl- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 395.4 (3.22) 251

4-(4-{[2-amino-6-(3-thienyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 387.4 (3.07) 252

4-(4-{[2-amino-6-(3-amino-4- methylphenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carbonitrile 410.5 (3.03) 253

4-(4-{[2-amino-6-(3,4-dichloro- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 450   (3.33) 254

4-(4-{[2-amino-6-(3-aminophenyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 414.2 (2.85) 255

4-(4-{[2-amino-6-(2-thienyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 405.1 (3.00) 256

4-(4-{[2-amino-6-(3-fluorophenyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 417.2 (2.96) 257

4-(4-{[2-amino-6-(4-chlorophenyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 433.1 (3.07) 258

4-[4-({2-amino-6-[3-(trifluoro- methyl)phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2- carboxamide 467.1 (3.11) 259

4-(4-{[2-amino-6-(4-butylphenyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 455.2 (3.25) 260

4-(4-{[2-amino-6-(2-fluoro- biphenyl-4-yl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carboxamide 493.1 (3.29) 261

4-(4-{[2-amino-6-(3-ethylphenyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 427.2 (3.11) 262

4-(4-{[2-amino-6-(5-isopropyl-2- methoxyphenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carboxamide 471.2 (3.25) 263

4-(4-{[2-amino-6-(2-methyl- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 413.2 (3.00) 264

4-(4-{[2-amino-6-(2,4-difluoro- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 435.1 (3.00) 265

4-[4-({2-amino-6-[3-(hydroxy- methyl)phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2- carboxamide 429.2 (2.89) 266

4-(4-{[2-amino-6-(4-isopropyl- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 441.2 (3.18) 267

4-(4-{[2-amino-6-(4-methyl- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 413.2 (3.07) 268

4-(4-{[2-amino-6-(3-methyl- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 413.2 (3.03) 269

4-(4-{[2-amino-6-(3-thienyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 405.1 (2.96) 270

4-(4-{[2-amino-6-(3-isopropyl- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 441.2 (3.22) 271

4-(4-{[2-amino-6-(3-amino-4- methylphenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carboxamide 428.2 (2.89) 272

4-(4-{[2-amino-6-(3,4-dichloro- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 467.1 (3.18) 273

4-(4-{[2-amino-6-(3-ethoxy- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 443.4 (2.81) 274

4-[4-({2-amino-6-[3-(trifluoro- methoxy)phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2- carbonitrile 465.1 (3.00) 275

4-[4-({2-amino-6-[2-(trifluoro- methoxy)phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2- carbonitrile 465.1 (2.92) 276

4-(4-{[2-amino-6-(3,5-difluoro- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carbonitrile 417.2 (2.89) 277

4-[4-({2-amino-6-[3-(trifluoro- methoxy)phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2- carboxamide 483.4 (2.89) 278

4-[4-({2-amino-6-[2-(trifluoro- methoxy)phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2- carboxamide 483.4 (2.81) 279

4-(4-{[2-amino-6-(3,5-difluoro- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 435.4 (2.74) 280

4-{3-[(2-amino-6-biphenyl-4- ylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxamide 475.5 (3.00) 281

4-[3-({2-amino-6-[3-(benzyloxy) phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2-carboxamide 505.5 (3.07) 282

6-(4-fluorophenyl)-N4*-{4-[(2- methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 388.4 (2.54) 283

4-(3-{[2-amino-6-(3-aminophenyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 414.4 (2.64) 284

4-(3-{[2-amino-6-(6-methoxy- pyridin-3-yl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carboxamide 430.4 (2.70) 285

4-(3-{[2-amino-6-(3-fluorophenyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 417.4 (2.77) 286

4-(3-{[2-amino-6-(2-fluorophenyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 417.4 (2.74) 287

4-[3-({2-amino-6-[4-(dimethyl- amino)phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2- carboxamide 442.5 (2.85) 288

4-(3-{[2-amino-6-(3-ethylphenyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 427.5 (2.88) 289

4-(3-{[2-amino-6-(5-isopropyl-2- methoxyphenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carboxamide 471.5 (3.00) 290

4-(3-{(2-amino-6-(2-methyl- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 413.5 (2.79) 291

4-(3-{[2-amino-6-(2-methoxy- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 429.5 (2.78) 292

4-(3-{[2-amino-6-(3-methoxy- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 429.5 (2.78) 293

4-(3-{[2-amino-6-(4-isopropyl- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 441.5 (2.97) 294

4-[3-({2-amino-6-[4-(cyano- methyl)phenyl]pyrimidin-4-yl}amino)phenoxy]pyridine-2- carboxamide 438.5 (2.75) 295

4-(3-{[2-amino-6-(4-methyl- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 413.5 (2.81) 296

4-(3-{[2-amino-6-(3-methyl- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 413.5 (2.80) 297

4-{3-[(2-amino-6-pyridin-3-yl- pyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxamide 400.4 (2.58) 298

4-(3-{[2-amino-6-(3-thienyl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 405.5 (2.72) 299

4-(3-{[2-amino-6-(3-isopropyl- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 441.5 (2.95) 300

4-(3-{[2-amino-6-(2,5- dimethoxyphenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carboxamide 459.5 (2.80) 301

4-(3-{[2-amino-6-(1H-pyrrol-2-yl) pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide  388.401 (2.69) 302

4-(3-{[2-amino-6-(3-amino-4- methylphenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2- carboxamide 428.5 (2.71) 303

4-(3-{[2-amino-6-(3,4-dichloro- phenyl)pyrimidin-4-yl]amino}phenoxy)pyridine-2-carboxamide 468.3 (2.92) 304

N4*-{4-[(2-methylpyridin-4-yl) oxy}phenyl}-6-(4-phenoxyphenyl)pyrimidine-2,4-diamine 462.5 (2.71) 305

6-[3-(dimethylamino)phenyl]- N4*-{4-[(2-methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4- diamine 413.5 (2.54) 306

3-[2-amino-6-({4-[(2-methyl- pyridin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]phenol 386.4 (2.48) 307

N4*-{4-[(2-methylpyridin-4-yl) oxy]phenyl}-6-[4-(trifluoro-methoxy)phenyl]pyrimidine-2,4- diamine 454.4 (2.71) 308

N-{4-[2-amino-6-({4-[(2-methyl- pyridin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]phenyl}acetamide 427.5 (2.47) 309

N4-{4-[(2-methylpyridin-4-yl)oxy] phenyl}-6-[2-(trifluoromethoxy)phenyl]pyrimidine-2,4-diamine 454.4 (2.61) 310

4-[2-amino-6-({4-[(2-methyl- pyridin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]phenol 386.4 (2.49) 311

6-(2-methylphenyl)-N4*-{4-[(2- methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 384.5 (2.54) 312

6-(6-methoxypyridin-3-yl)-N4*- {4-[(2-methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 401.4 (2.50) 313

6-(4-aminophenyl)-N4*-{4-[(2- methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 385.4 (2.47) 314

N4*-{4-[(2-methylpyridin-4-yl) oxy]phenyl}-6-[3-(trifluoro-methyl)phenyl]pyrimidine-2,4- diamine 438.4 (2.66) 315

6-(3-fluorophenyl)-N4*-{4-[(2- methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 388.4 (2.55) 316

6-(3-methoxyphenyl)-N4*-{4-[(2- methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 400.5 (2.57) 317

6-(4-ethylphenyl)-N4*-{4-[(2- methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 398.5 (2.66) 318

6-[4-(dimethylamino)phenyl]-N4*- {4-[(2-methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 413.5 (2.63) 319

6-(3,4-dimethoxyphenyl)-N4*-{4- [(2-methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 430.5 (2.55) 320

6-(3-aminophenyl)-N4*-{4-[(2- methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 385.4 (2.41) 321

6-(3-furyl)-N4*-{4-[(2-methyl- pyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 360.4 (2.49) 322

6-(2-aminophenyl)-N4*-{4-[(2- methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 385.4 (2.49) 323

6-(3-amino-4-methylphenyl)-N4*- {4-[(2-methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 399.5 (2.48) 324

6-(3-isopropoxyphenyl)-N4*-{4- [(2-methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine 428.5 (2.68) 325

N4*-{4-[(2-methylpyridin-4-yl) oxy]phenyl}-6-[3-(trifluoro-methoxy)phenyl]pyrimidine-2,4- diamine 454.4 (2.69) 326

4-[2-amino-6-({4-[(2-cyano- pyridin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]phenyl sulfamate 327

3-[2-amino-6-({4-[(2-methyl- pyridin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]phenyl sulfamate 328

3-[2-amino-6-({4-[(2-cyano- pyridin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]phenyl sulfamate 329

4-[2-amino-6-({4-[(2-methyl- pyridin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]phenyl sulfamate 330

3-{2-amino-6-[(4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}phenyl sulfamate 331

4-{2-amino-6-[(4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}-3- methylphenyl sulfamate 332

4-[2-amino-6-({4-[(2-chloro- pyridin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]phenyl sulfamate 485.3 (2.42) 333

4-{2-amino-6-[(4-{[2-(trifluoro- methyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}phenyl dimethylsulfamate 334

3-[2-amino-6-({4-[(2-chloro- pyridin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]phenyl sulfamate

Example 335 Preparation of6-(2,6-dimethylphenyl)-N⁴-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine

To a mixture of6-chloro-N⁴-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine(1.0 g, 2.6 mmol; available by condensation of2-amino-4,6-dichloropyrimidine and{4-[(2-trifluoromethylpyridin-4-yl)oxy]phenyl}amine, described in WO2003/099771, which is hereby incorporated by reference) and1,3-dimethylphenylboronic acid (786 mg, 5.2 mmol) in DMF (13 mL) wasadded aqueous Na₂CO₃ (2 M, 3.9 mL) andtetrakis(triphenylphosphin)palladium (0) (303 mg, 0.26 mmol). Theresulting mixture was degassed for 10 min before it was placed in amicrowave reactor (Emrys optimizer by Personal Chemistry) at 150° C. for20 min. The resulting mixture was cooled to rt before it was filteredand insoluble material was rinsed with DMF. The filtrate wasconcentrated under vacuo and dissolved in EtOAc. The resulting mixturewas washed with water and the organic layer was dried over Na₂SO₄.Removal of the solvent under vacuo gave the crude material, which waspurified with 40 M biotage eluting with Hex/EtOAc (1/1) to provide thetitle compound as an off-white solid (657 mg, 56%): ¹H NMR (DMSO-d₆): δ9.27 (s, 1H), 8.59 (d, 1H), 7.86-7.90 (m, 2H), 7.35 (d, 1H), 7.04-7.17(m, 6H), 6.35 (s, 2H), 5.86 (s, 1H), 2.10 (s, 6H) ppm; MS ES 452 (M+H)⁺,RT=2.76 min.

Example 336 Preparation of6-(6-aminopyridin-3-yl)-N⁴-{4-[(2-methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine

Step 1: Preparation of {4-[(2-Methylpyridin-4-yl)oxy]phenyl}amine

4-aminophenol (44.9 g, 410 mmol) was added to the 1 L 3-neck flask anddissolved with N,N-dimethylacetamide (600 mL). The stirred mixture wasthen cooled to 9° C. and potassium t-butoxide (46.18 g, 410 mmol) wasadded portionwise; the solution turned green and solidified beforepotassium t-butoxide addition was completed. Stirring was reestablishedand a solution containing the 4-chloro-2-picoline (50 g, 390 mmol) inN,N-dimethylacetamide (400 mL) was slowly added and the mixture washeated at 90° C. for 17 h. The mixture was then allowed to cool to 45°C., filtered and concentrated to near dryness in vacuo to leave brownresidue. The residue was slowly added to vigorously stirred water (1 L)and the suspension was stirred for 1 hr. The solids were then collectedby suction filtration and washed with small amount of isopropanol, etherand dried to afford {4-[(2-Methylpyridin-4-yl)oxy]phenyl}amine (49.9 g,64%) as light tan solid. ¹H NMR (DMSO-d₆)

8.21 (d, 1H), 6.78 (d, 2H), 6.57-6.63 (m, 4H), 5.10 (s, 2H), 2.35 (s,3H); MS ES 201 (M+H)⁺, calcd 201, RT=1.04 min.

Step 2: Preparation of6-chloro-N⁴-(4-{[2-methylpyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine

{4-[(2-Methylpyridin-4-yl)oxy]phenyl}amine (47.5 g, 237 mmol) and2-amino-4,6-dichloropyrimidine (40.8 g, 249 mmol) were suspended inwater (900 mL) and 2-propanol (300 mL). 2M aqueous hydrochloric acidsolution (23.7 mL) was then added and the mixture was then heated at 95°C. for 17 h. The mixture was then allowed to come to rt and solids werecollected by suction filtration and washed with small amount ofisopropanol. The solids were then resuspended in DMF and heated at 90°C. Triethylamine (20 mL) was then added and the mixture was stir foradditional 10 min at 90° C. Water was then added in excess untilcloudiness persisted at temperature. This was cooled to about 5° C. andprecipitate formed were collected by suction filtration, washed withwater and dried in vacuum oven at 40° C. to afford desired product (50g, 64%) as light tan solid. ¹H NMR (DMSO-d₆)

9.40 (s, 1H), 8.27 (d, 1H), 7.76 (d, 2H), 7.06 (d, 2H), 6.75 (brs, 2H),6.72 (d, 1H), 6.66 (s, 1H), 5.98 (s, 1H); MS ES 328 (M+H)⁺, calcd 328,RT=1.45 min.

Step 3: Preparation of the Title Compound

To a mixture of6-chloro-N⁴-(4-{[2-methylpyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine(2.0 g, 6.1 mmol) and2-Amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.6 g,7.3 mmol) in DMF (30 mL) was added aqueous Na₂CO₃ (2 M, 9.0 mL) and1,1′-bis(diphenylphosphino)ferrocenepalladium (II) chloride (223 mg, 0.3mmol). The resulting mixture was degassed for 10 min before it washeated at 80° C. overnight. The resulting mixture was cooled to rtbefore it was concentrated under vacuo and dissolved in EtOAc. Theresulting mixture was washed with water and brine and the organic layerwas dried over Na₂SO₄. Removal of the solvent under vacuo gave the crudematerial, which was purified with 40 M biotage eluting with 100% EtOAcfirst and then with 95% CH₂Cl₂ and 5% 2 N ammonia in MeOH to provide thetitle compound as an off-white solid (1340 mg, 57%): ¹H NMR (DMSO-d6): δ9.20 (s, 1H), 8.51 (dd, 1H), 8.27 (d, 1H), 7.81-7.88 (m, 3H), 7.03-7.06(m, 2H), 6.72 (d, 1H), 6.68 (dd, 1H), 6.47 (dd, 1H), 6.33 (s, 1H), 6.32(s, 2H), 6.23 (s, 2H), 2.39 (s, 3H) ppm; MS ES 386 (M+H)⁺, RT=1.06 min.

Example 337 Preparation of Preparation ofN⁶-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)-4,5′-bipyrimidine-2,6-diamine

A suspension of6-chloro-N⁴-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine(150 mg, 0.39 mmol, see example 335), pyrimidin-5-ylboronic acid (97.37mg, 0.79 mmol), tetrakis(triphenylphosphin)palladium(0) (45.41 mg, 0.04mmol), sodium carbonate (208.23 mg, 1.96 mmol) in 2.5 ml of anhydrousDMF was degassed for 10 min. The mixture was reacted under microwavecondition at 180° C. for 20 min. The reaction mixture was filtered andconcentrated. The residue was extracted with EtOAc (6 ml) and washedwith 1 M NaOH solution (1 mL×2) and water (1 mL×3). The organic layerwas dried to furnish 129 mg of the crude product. The crude product waspurified by prep-TLC (Hex:EtOAc=2:8) to give 38 mg (23%) of the titlecompound as a yellow solid. ¹H NMR (CD₃OD): δ 9.28 (s, 2H), 9.20 (s,1H), 8.54 (d, 1H), 7.88 (d, 2H), 7.32 (d, 1H), 7.15 (m, 3H), 6.56 (s,1H) ppm; MS ES 426 (M+H)⁺, calc. 426, RT=2.35 min; TLC(Hexane:EtOAc=1:9) R_(f)=0.25.

Example 338 Preparation of6-phenyl-N⁴-(4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine

Step 1. Preparation of 4-chloro-2-(trifluoromethyl)pyrimidine

2-(trifluoromethyl)pyrimidin-4-ol (3.0 g, 18.28 mmol, available fromFluorochem Ltd., UK) was suspended in POCl₃ (17 mL) andN,N-dimethylaniline (1.16 mL, 9.14 mmol) was added. The mixture was thenheated to reflux for 2 hr. The mixture was cooled and poured intocrushed ice, then extracted twice with ether. The combined organiclayers were washed with small amount of water, dried (Na₂SO₄), andconcentrated to give 4-chloro-2-trifluoromethyl)pyrimidine (2.5 g, 71%)as light yellow oil (2.5 g, 71%). ¹H NMR (DMSO-d₆) δ 9.05 (d, 1H), 8.14(d, 1H); MS EI 182 (M)⁺, calcd 482, LCMS RT=2.25, GCMS RT=3.2 min.

Step 2. Preparation of 4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}aniline

To a solution of 4-aminophenol (1.64 g, 15 mmol) in DMF (40 mL) wasadded potassium tert-butoxide (1.69 g, 15 mmol) and the resultingmixture was stirred at room temp for 15 min.4-chloro-2-(trifluoromethyl)pyrimidine in DMF (10 mL) was then added andthe resulting mixture was stirred at room temp for 16 h. Water was thenadded and the mixture was extracted with ethyl acetate, dried overanhydrous sodium sulfate and concentrated in vacuo. The crude waspurified using Biotage flash 40M (2:1, Hexane, Ethyl acetate) to afford4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}aniline (2.2 g, 63%). ¹H NMR(DMSO-d₆)

8.78 (d, 1H), 7.16 (d, 1H), 6.90 (d, 2H), 6.60 (d, 2H), 5.17 (brs, 2H);MS ES 256 (M+H)^(÷), calcd 256, RT=2.42 min.

Step 3. Preparation of the Title Compounds

4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}aniline (1.0 g, 3.9 mmol) and4-chloro-6-phenylpyrimidin-2-amine (806 mg, 3.9 mmol) were suspended inwater (39 mL) and isopropanol (13 mL) and the mixture was heated at 95°C. for 17 h. After cooling to rt, the mixture was neutralized with 1 Naqueous sodium hydroxide and stirred for 20 min. The precipitate werecollected by filtration to afford6-phenyl-N⁴-(4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine(1.2 g, 72%) as a yellow solid. ¹H NMR (DMSO-d₆)

9.35 (s, 1H), 8.85 (d, 1H), 7.85-7.91 (m, 4H), 7.42-7.47 (m, 3H), 7.30(d, 1H), 7.18 (d, 2H), 6.48 (s, 1H), 6.38 (brs, 2H); MS ES 425 (M+H)⁺,calcd 425, RT=2.53 min.

Example 339 Preparation of6-(6-aminopyridin-3-yl)-N⁴-(4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine

6-(6-aminopyridin-3-yl)-N⁴-(4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine was prepared by amethod analogous to that described for Example 338 (step 3). ¹H NMR(DMSO-d₆)

8.88 (d, 1H), 8.46 (d, 1H), 7.81-7.94 (m, 6H), 7.38 (d, 1H), 7.30 (d,2H), 6.63 (brs, 2H), 6.46 (brs, 2H); MS ES 441 (M+H)⁺, calcd 441,RT=1.98 min.

Cytotoxic Activity of the Invention Compounds

The following section describes an assay that can be used tocharacterize compounds of the invention, e.g., to test for the cytotoxicactivity of compounds on cells.

Human tumor cells, e.g., HCT116 cells, are seeded in a 96-well plate at3.0×10³ cells/well and grown in 100 μl of RPMI complete media(Invitrogen Corporation, Grand Island, N.Y.) containing 10% fetal bovineserum (Hyclone, Logan, Utah) and 10 mM HEPES and at 37° C. for 16 h inan incubator with 5% CO₂. To each well, 50 μl of additional growth mediacontaining 20 μM to 60 nM concentrations of compound with 0.2% DMSO isadded. Cells are grown for another 72 h at 37° C. 20 μl of Alamar Blue(Trek Diagnostic Systems, Inc., Cleveland, Ohio) reagent is added toeach well and incubated for 4 h at 37° C. Plates are read in aSpectraMax Gemini (Molecular Devices, CA) with 544 nm excitation and 590nm emission wavelength. IC₅₀ values are determined by linear regressionanalysis of log drug concentration versus percent inhibition.

Representative compounds of this invention were tested for cytotoxicityusing the above-described assay procedure with the following results:

Examples 1, 2, 3, 4, 6, 7, 8, 9, 11, 13, 19, 21, 33, 34, 35, 37, 38, 39,40, 45, 46, 48, 49, 50, 51, 52, 53, 58, 62, 63, 64, 66, 67, 69, 76, 80,84, 88, 92, 94, 95, 96, 97, 98, 99, 113, 114, 116, 117, 118, 119, 120,121, 123, 124, 125, 127, 129, 133, 134, 137, 139, 140, 142, 143, 145,146, 149, 150, 151, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162,163, 164, 165, 166, 167, 168, 169, 170, 171, 173, 174, 175, 177, 179,180, 181, 183, 185, 187, 188, 190, 191, 192, 193, 195, 196, 199, 200,202, 204, 205, 206, 208, 209, 210, 211, 212, 213, 214, 215, 218, 219,223, 227, 228, 229, 233, 234, 238, 240, 241, 246, 249, 250, 251, 252,254, 259, 261, 262, 263, 264, 266, 267, 268, 269, 271, 273, 275, 278,282, 288, 290, 292, 296, 298, 302, 305, 310, 311, 312, 313, 315, 316,317, 318, 320, 321, 323 and 332 show an IC₅₀ of less than or equal to500 nM in the HCT116 cytotoxic activity assay:

Examples 5, 10, 12, 23, 26, 30, 32, 41, 42, 47, 60, 61, 65, 68, 70, 73,75, 79, 82, 85, 86, 89, 90, 91, 100, 101, 105, 107, 109, 112, 115, 128,130, 131, 132, 135, 136, 138, 141, 144, 148, 152, 172, 176, 189, 194,197, 198, 201, 203, 207, 220, 222, 226, 230, 231, 232, 235, 239, 242,243, 245, 247, 248, 256, 257, 258, 276, 279, 281, 283, 284, 286, 291,294, 297, 300, 304, 306, 308, 309, 319, 322, 324, and 325 show an IC₅₀greater than 500 nM but less than or equal to 2 μM in the HCT116cytotoxic activity assay.

Examples, 43, 44, 71, 72, 74, 77, 81, 83, 87, 93, 106, 108, 110, 111,122, 126, 147, 178, 216, 217, 221, 224, 225, 236, 237, 244, 253, 255,260, 265, 270, 272, 274, 277, 280, 285, 287, 289, 293, 295, 299, 301,303, 307, and 314 show an IC₅₀ greater than 2 μM in the HCT116 cytotoxicactivity assay.

Exemplary IC₅₀s of further examples are shown in the table below.

Example number HCT-116 IC₅₀ [nM] 335 62 336 6 337 135 338 17 339 3

Other embodiments of the invention will be apparent to the skilled inthe art from a consideration of this specification or practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with the true scope and spiritof the invention being indicated by the following claims.

1. A compound having the structure

wherein R¹ represents H, (C₁-C₃)alkyl, or cyclopropyl; R² represents(C₁-C₃)alkyl, cyclopropyl, O(C₁-C₃)alkyl, or NR³R⁴ wherein R³ and R⁴ areH, (C₁-C₃)alkyl, or cyclopropyl; R^(2a) represents H or halogen; Mrepresents CH or N; L represents a carbonyl group, O, NR⁵, CR⁶R⁷, or(C₂-C₃)alkylenyl which is optionally substituted up to twice by groupsindependently selected from halogen and OH; wherein R⁵ is H or(C₁-C₃)alkyl; and R⁶ and R⁷ are independently H, CH₃, halogen, or OH; Jrepresents an aromatic or heteroaromatic ring selected from the groupconsisting of

Y represents an aromatic or heteroaromatic ring selected from the groupconsisting of

wherein R⁸ represents H or (C₁-C₃)alkyl; G″ represents a substituentselected from the group consisting of (C₁-C₃)alkyl, cyclopropyl,O(C₁-C₃)alkyl, halogen, CF₃, CN and CO₂R⁹; wherein R⁹ represents H or(C₁-C₃)alkyl; and m represents the number of substituents G″, and is 0,1, or 2; G represents a substituent located on ring J; G′ represents asubstituent located on ring Y; n represents the number of substituentsG; and n′ represents the number of substituents G′; n and n′ areindependently 0, 1, 2, or 3, subject to the provisos that 1) ring J andring Y each may be substituted independently up to 3 times bysubstituents listed below as numbers G1-G2, to a maximum total of 4substituents on rings J and Y, 2) ring J and ring Y each may besubstituted independently up to 2 times by substituents listed below asnumbers G3-G11, to a maximum total of 3 substituents on rings J and Y,and 3) ring J and ring Y each may be substituted independently once by asubstituent selected from those listed below as numbers G12-G37; andsubject to the further provisos 4) when J is phenyl, G is other than OHor alkylthio; and when J is phenyl or pyridyl, n is 1, 2, or 3; 5) whenJ is phenyl, and G is G4 shown below, then R² is NR³R⁴; G and G′moieties are independently selected from the group consisting of: G1)halogen; G2) O(C₁-C₄)alkyl which optionally is substituted up to twotimes by O(C₁-C₂)alkyl; G3) OH; G4) (C₁-C₅)alkyl, which is optionallysubstituted independently up to two times by groups selected fromhydroxyl and cyano, or up to three times by halogen; G5) OCF₃; G6)NHC(O)(C₁-C₃)alkyl; G7) NHSO₂(C₁-C₃)alkyl; G8) NR¹⁰R¹¹, wherein R¹⁰ andR¹¹ are independently selected from H, CH₃, cyclopropyl, benzyl, NR¹²R¹³wherein R¹² and R¹³ are independently H or (C₁-C₃)alkyl, provided thatboth R¹⁰ and R¹¹ are not NR¹²R¹³ simultaneously, and (C₂-C₄)alkyl whichis optionally substituted up to three times by halogen, and up to twotimes by substituent groups independently selected from hydroxyl,O(C₁-C₃)alkyl, and NR¹⁴R¹⁵, wherein R¹⁴ and R¹⁵ are independently H or(C₁-C₃)alkyl, or R¹⁴ and R¹⁵ can join to form a heterocycle of formula

 wherein Q represents CH₂, O, or NR¹⁶, and R¹⁶ represents H or(C₁-C₃)alkyl, or R¹⁰ and R¹¹ may be joined to form a saturated5-6-membered N-containing ring which is optionally substituted up to twotimes by OH, NR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸ are H or (C₁-C₃)alkyl, or by(C₁-C₃)alkyl which is optionally substituted up to two times by halogen,OH, or O(C₁-C₃)alkyl; G9) (CH₂)_(a)—NR¹⁹R²⁰ wherein R¹⁹ and R²⁰ areindependently H, (C₁-C₅)alkyl, or (C₃-C₆)cycloalkyl, or may be joined toform a saturated 5-6-membered N-containing ring; and the subscript “a”is an integer of 1-4; G10)

 wherein Q′ is O or NR²¹; R²¹ is H, (C₁-C₃)alkyl, or cyclopropyl; andthe subscript “b” is an integer of 1-3; G11) CH₂NR²²(CH₂)_(c)OCH₃wherein R²² is H, (C₁-C₃)alkyl, or cyclopropyl; and the subscript “c” isan integer of 2-4; G12) OSO₂NR²³R²⁴ wherein R²³ and R²⁴ independentlyrepresent H, CH₃, or (C₂-C₄)alkyl which may optionally be substitutedonce by OH or NR²⁵R²⁶, wherein R²⁵ and R²⁶ independently represent H or(C₁-C₃)alkyl; G13) CN; G14) NO₂; G15) cyclopropyl; G16) OR²⁷, whereinR²⁷ represents phenyl or benzyl; G17) S(C₁-C₃)alkyl; G18)CH═CH—(CH₂)₁₋₃—OR⁵; wherein R⁵ represents H or (C₁-C₃)alkyl; G19)

G20)

G21) C(O)NR²⁸R²⁹, wherein R²⁸ and R²⁹ are independently selected from H,cyclopropyl, provided that both R²⁸ and R²⁹ are not simultaneouslycyclopropyl,

 provided that this group does not constitute both R²⁸ and R²⁹simultaneously, and (C₁-C₃)alkyl which is optionally substituted up totwo times by OH; or R²⁸ and R²⁹ may be joined to form a saturated5-6-membered N-containing ring which is optionally substituted up to twotimes by OH, or by (C₁-C₃)alkyl which in turn is optionally substitutedup to two times by OH or O(C₁-C₃)alkyl; G22)

 wherein Q″ is O or NR³⁰, and R³⁰ is H, cyclopropyl, or (C₁-C₃)alkylwhich is optionally substituted once by halogen, OH, or O(C₁-C₃)alkyl;G23) O—(CH₂)_(d)—NR³¹R³² wherein R³¹ and R³² are independently H,(C₁-C₃)alkyl, or cyclopropyl, or may be joined to form a saturated5-6-membered N-containing ring; and the subscript “d” is an integer of2-4; G24)

 wherein the subscript “e” is an integer of 2-3; and Q′″ is O or NR³³;and R³³ is H, (C₁-C₃)alkyl, or cyclopropyl; G25)

 wherein Q^(iv) is O or NR³⁴; and R³⁴ is H, (C₁-C₃)alkyl, orcyclopropyl; G26) C(O)NR³⁵(CH₂)_(f)OR³⁶ wherein R³⁵ is H, (C₁-C₃)alkyl,or cyclopropyl; R³⁶ is (C₁-C₆)alkyl optionally substituted up to twotimes by halogen, OH, or O(C₁-C₃)alkyl, and the subscript “f” is aninteger of 2-4; G27) CO₂R³⁷ wherein R³⁷ is H or (C₁-C₃)alkyl; G28)phenyl, which is optionally substituted by up to 2 groups selected fromhalogen, (C₁-C₃)alkyl, OR³⁸, CN, CF₃, and NR³⁹R⁴⁰ wherein R³⁸ representsH or (C₁-C₃)alkyl; and R³⁹ and R⁴⁰ represent H or (C₁-C₃)alkyl; G29)NR⁴¹SO₂NR⁴²R⁴³ wherein R⁴¹ represents H, or (C₁-C₄)alkyl, and R⁴² andR⁴³ independently represent H, CH₃, or (C₂-C₃)alkyl which may optionallybe substituted once by —OH or NR⁴⁴R⁴⁵, wherein R⁴⁴ and R⁴⁵ independentlyrepresent H or (C₁-C₃)alkyl; G30) OC(O)—CH₂—NR⁴⁶R⁴⁷ wherein R⁴⁶ and R⁴⁷independently represent H, (C₁-C₃)alkyl, or CO₂(t-butyl), provided thatR⁴⁶ and R⁴⁷ are not both simultaneously CO₂(t-butyl); G31) N(R⁴⁸)C(O)R⁴⁹wherein R⁴⁸ represents H or (C₁-C₃)alkyl; and R⁴⁹ represents(CH₂)₁₋₃—CO₂H, O(C₂-C₄)alkyl, (CH₂)₁₋₄—NR⁵⁰R⁵¹ wherein  R⁵⁰ and R⁵¹independently represent H or (C₁-C₃)alkyl, or CH(R⁵²)—NR⁵³R⁵⁴ wherein R⁵² represents (CH₂)₁₋₄—NH₂, CH₂OH, CH(CH₃)OH, or (C₁-C₃)alkyl; and R⁵³ and R⁵⁴ independently represent H or (C₁-C₃)alkyl; G32)C(O)—(C₁-C₃)alkyl; G33) (CH₂)_(g)—N(R⁵⁵)—C(O)—R⁵⁶ wherein g represents1, 2, or 3; R⁵⁵ represents H or (C₁-C₃)alkyl; R⁵⁶ represents(C₁-C₃)alkyl optionally substituted up to two times by OR⁵⁷ or NR⁵⁸R⁵⁹,wherein  R⁵⁷ represents H or (C₁-C₃)alkyl, and  R⁵⁸ and R⁵⁹ eachrepresents H or (C₁-C₃)alkyl, or R⁵⁶ represents

 wherein R⁶⁰ represents halogen, (C₁-C₃)alkyl, O(C₁-C₃)alkyl, CN, OH,CF₃, or NR⁶¹R⁶², wherein  R⁶¹ and R⁶² represent H or (C₁-C₃)alkyl; and hrepresents 0, 1, or 2; G34) (CH₂)_(i)—N(R⁶³)—C(O)—NR⁶⁴R⁶⁵ wherein irepresents 1, 2, or 3; R⁶³ represents H or (C₁-C₃)alkyl; R⁶⁴ and R⁶⁵each represents H or (C₁-C₃)alkyl; or R⁶⁴ and R⁶⁵ may be joined to form

 wherein Q^(V) represents CH₂, O or NR⁶⁶ wherein  R⁶⁶ represents H or(C₁-C₃)alkyl; G35)

 wherein j represents 1, 2, or 3; R⁶⁷ represents H or (C₁-C₃)alkyl; andR⁶⁸ represents H or (C₁-C₃)alkyl; G36) (CH₂)_(k)—N(R⁶⁹)—SO₂—R⁷⁰ whereink represents 1, 2, or 3; R⁶⁹ represents H or (C₁-C₃)alkyl; and R⁷⁰represents (C₁-C₄)alkyl, or phenyl which is optionally substituted up toperhalo by halogen or up to three times by OR⁷¹, CN, CF₃, or NR⁷²R⁷³,wherein R⁷¹ represents H or (C₁-C₃)alkyl; and R⁷² and R⁷³ eachrepresents H or (C₁-C₃)alkyl; G37) CH═CH—(CH₂)₁₋₃—NR⁷⁴R⁷⁵ wherein R⁷⁴and R⁷⁵ represent H or (C₁-C₃)alkyl; or a pharmaceutically acceptablesalt, solvate, solvate of a salt, or stereoisomer thereof.
 2. Thecompound of claim 1 wherein R¹ represents H; M represents CH; Jrepresents a heteroaromatic ring selected from the group consisting of

Y represents an aromatic or heteroaromatic ring selected from the groupconsisting of

n and n′ are independently 0, 1, 2, or 3, subject to the provisosthat 1) ring J and ring Y each may be substituted independently up to 3times by substituents listed below as numbers G1-G2, to a maximum totalof 4 substituents on rings J and Y, 2) ring J and ring Y each may besubstituted independently up to 2 times by substituents listed below asnumbers G3-G5 and G8, to a maximum total of 3 substituents on rings Jand Y, and 3) ring J and ring Y each may be substituted independentlyonce by a substituent selected from those listed below as numbers G12,G13, G22, G29, and G31; and subject to the further proviso 4) when J ispyridyl, n is 1, 2, or 3; and proviso 5 does not apply; G and G′moieties are independently selected from the group consisting of: G1)halogen; G2) O(C₁-C₄)alkyl which optionally is substituted up to twotimes by O(C₁-C₂)alkyl; G3) OH; G4) (C₁-C₅)alkyl, which is optionallysubstituted independently up to two times by groups selected fromhydroxyl and cyano, or up to three times by halogen; G5) OCF₃; G8)NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently selected from H, CH₃,cyclopropyl, benzyl, NR¹²R¹³ wherein  R¹² and R¹³ are independently H or(C₁-C₃)alkyl, provided that both R¹⁰ and R¹¹ are not NR¹²R¹³simultaneously, and (C₂-C₄)alkyl which is optionally substituted up tothree times by halogen, and up to two times by substituent groupsindependently selected from hydroxyl, O(C₁-C₃)alkyl, and NR¹⁴R¹⁵,wherein  R¹⁴ and R¹⁵ are independently H or (C₁-C₃)alkyl, or  R¹⁴ andR¹⁵ can join to form a heterocycle of formula

 wherein  Q represents CH₂, O, or NR¹⁶, and  R¹⁶ represents H or(C₁-C₃)alkyl, or R¹⁰ and R¹¹ may be joined to form a saturated5-6-membered N-containing ring which is optionally substituted up to twotimes by OH, NR¹⁷R¹⁸, wherein  R¹⁷ and R¹⁸ are H or (C₁-C₃)alkyl, or by(C₁-C₃)alkyl which is optionally substituted up to two times by halogen,OH, or O(C₁-C₃)alkyl; G12) OSO₂NR²³R²⁴ wherein R²³ and R²⁴ independentlyrepresent H, CH₃, or (C₂-C₄)alkyl which may optionally be substitutedonce by OH or NR²⁵R²⁶ wherein R²⁵ and R²⁶ independently represent H or(C₁-C₃)alkyl; G13) CN; G22)

 wherein Q″ is O or NR³⁰, and R³⁰ is H, cyclopropyl, or (C₁-C₃)alkylwhich is optionally substituted once by halogen, OH, or O(C₁-C₃)alkyl;G29) NR⁴¹SO₂NR⁴²R⁴³ wherein R⁴¹ represents H, or (C₁-C₄)alkyl, and R⁴²and R⁴³ independently represent H, CH₃, or (C₂-C₃)alkyl which mayoptionally be substituted once by —OH or NR⁴⁴R⁴⁵, wherein R⁴⁴ and R⁴⁵independently represent H or (C₁-C₃)alkyl; and G31) N(R⁴⁸)C(O)R⁴⁹wherein R⁴⁸ represents H or (C₁-C₃)alkyl; and R⁴⁹ represents(CH₂)₁₋₃—CO₂H, O(C₂-C₄)alkyl, (CH₂)₁₋₄—NR⁵⁰R⁵¹ wherein  R⁵⁰ and R⁵¹independently represent H or (C₁-C₃)alkyl, or  CH(R⁵²)—NR⁵³R⁵⁴ wherein R⁵² represents (CH₂)₁₋₄—NH₂, CH₂OH, CH(CH₃)OH, or (C₁-C₃)alkyl; and R⁵³ and R⁵⁴ independently represent H or (C₁-C₃)alkyl.
 3. The compoundof claim 2 wherein R¹ represents H; R² represents O(C₁-C₃)alkyl or NR³R⁴wherein R³ and R⁴ are H or (C₁-C₃)alkyl; R^(2a) represents H; Lrepresents O or CR⁶R⁷ wherein R⁶ and R⁷ are independently H, CH₃, or OH;G″ represents a substituent selected from the group consisting ofO(C₁-C₃)alkyl, halogen, and CF₃; n and n′ are independently 0 or 1, andprovisos 1-3 do not apply; G and G′ moieties are independently selectedfrom the group consisting of: G1) Cl or F; G2) O(C₁-C₃)alkyl; G3) OH;G4) (C₁-C₃)alkyl, which is optionally substituted up to three times byhalogen; G5) OCF₃; G8) NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independentlyselected from H, CH₃, cyclopropyl, benzyl, NR¹²R¹³ wherein  R¹² and R¹³are independently H or (C₁-C₃)alkyl, provided that both R¹⁰ and R¹¹ arenot NR¹²R¹³ simultaneously, and (C₂-C₄)alkyl which is optionallysubstituted up to three times by halogen, and up to two times bysubstituent groups independently selected from hydroxyl, O(C₁-C₃)alkyl,and NR¹⁴R¹⁵, wherein  and R¹⁵ are independently H or (C₁-C₃)alkyl, or R¹⁴ and R¹⁵ can join to form a heterocycle of formula

 wherein  Q represents CH₂, O, or NR¹⁶, and  R¹⁶ represents H or(C₁-C₃)alkyl, G12) OSO₂NR²³R²⁴ wherein R²³ and R²⁴ independentlyrepresent H, CH₃, or (C₂-C₄)alkyl which may optionally be substitutedonce by OH or NR²⁵R²⁶, wherein R²⁵ and R²⁶ independently represent H or(C₁-C₃)alkyl; G13) CN; G22)

 wherein Q″ is O or NR³⁰, and R³⁰ is H or (C₁-C₃)alkyl; and G31)N(R⁴⁸)C(O)R⁴⁹ wherein R⁴⁸ represents H or (C₁-C₃)alkyl; and R⁴⁹represents (CH₂)₁₋₃—CO₂H, O(C₂-C₄)alkyl, (CH₂)₁₋₄—NR⁵⁰R⁵¹ wherein  R⁵⁰and R⁵¹ independently represent H or (C₁-C₃)alkyl, or CH(R⁵²)—NR⁵³R⁵⁴wherein  R⁵² represents (CH₂)₁₋₄—NH₂, CH₂OH, CH(CH₃)OH, or (C₁-C₃)alkyl;and  R⁵³ and R⁵⁴ independently represent H or (C₁-C₃)alkyl.
 4. Thecompound of claim 1 wherein R¹ represents H; M represents CH; Jrepresents a heteroaromatic ring selected from the group consisting of

Y represents an aromatic or heteroaromatic ring selected from the groupconsisting of

n and n′ are independently 0, 1, 2, or 3, subject to the provisosthat 1) ring J and ring Y each may be substituted independently up to 3times by substituents listed below as numbers G1-G2, to a maximum totalof 4 substituents on rings J and Y, 2) ring J and ring Y each may besubstituted independently up to 2 times by substituents listed below asnumbers G3-G5 and G8, to a maximum total of 3 substituents on rings Jand Y, and 3) ring J and ring Y each may be substituted independentlyonce by a substituent selected from those listed below as numbers G12,G21, G25, G26, and G31; and subject to the further proviso 4) when J ispyridyl, n is 1, 2, or 3; and proviso 5 does not apply; G and G′moieties are independently selected from the group consisting of: G1)halogen; G2) O(C₁-C₄)alkyl which optionally is substituted up to twotimes by O(C₁-C₂)alkyl; G3) OH; G4) (C₁-C₅)alkyl, which is optionallysubstituted independently up to two times by groups selected fromhydroxyl and cyano, or up to three times by halogen; G5) OCF₃; G8)NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently selected from H, CH₃,cyclopropyl, benzyl, NR¹²R¹³ wherein  R¹² and R¹³ are independently H or(C₁-C₃)alkyl, provided that both R¹⁰ and R¹¹ are not NR¹²R¹³simultaneously, and (C₂-C₄)alkyl which is optionally substituted up tothree times by halogen, and up to two times by substituent groupsindependently selected from hydroxyl, O(C₁-C₃)alkyl, and NR¹⁴R¹⁵,wherein  R¹⁴ and R¹⁵ are independently H or (C₁-C₃)alkyl, or  R¹⁴ andR¹⁵ can join to form a heterocycle of formula

 wherein  Q represents CH₂, O, or NR¹⁶, and  R¹⁶ represents H or(C₁-C₃)alkyl, or R¹⁰ and R¹¹ may be joined to form a saturated5-6-membered N-containing ring which is optionally substituted up to twotimes by OH, NR¹⁷R¹⁸, wherein  R¹⁷ and R¹⁸ are H or (C₁-C₃)alkyl, or by(C₁-C₃)alkyl which is optionally substituted up to two times by halogen,OH, or O(C₁-C₃)alkyl; G12) OSO₂NR²³R²⁴ wherein R²³ and R²⁴ independentlyrepresent H, CH₃, or (C₂-C₄)alkyl which may optionally be substitutedonce by OH or NR²⁵R²⁶ wherein R²⁵ and R²⁶ independently represent H or(C₁-C₃)alkyl; G21) C(O)NR²⁸R²⁹, wherein R²⁸ and R²⁹ are independentlyselected from H, cyclopropyl, provided that both R²⁸ and R²⁹ are notsimultaneously cyclopropyl,

 provided that this group does not constitute both  R²⁸ and R²⁹simultaneously, and (C₁-C₃)alkyl which is optionally substituted up totwo times by OH; or R²⁸ and R²⁹ may be joined to form a saturated5-6-membered N-containing ring which is optionally substituted up to twotimes by OH, or by (C₁-C₃)alkyl which in turn is optionally substitutedup to two times by OH or O(C₁-C₃)alkyl; G25)

 wherein Q^(iv) is O or NR³⁴; and R³⁴ is H, (C₁-C₃)alkyl, orcyclopropyl; G26) C(O)NR³⁵(CH₂)_(f)OR³⁶ wherein R³⁵ is H, (C₁-C₃)alkyl,or cyclopropyl; R³⁶ is (C₁-C₆)alkyl optionally substituted up to twotimes by halogen, OH, or O(C₁-C₃)alkyl, and the subscript “f” is aninteger of 2-4; and G31) N(R⁴⁸)C(O)R⁴⁹ wherein R⁴⁸ represents H or(C₁-C₃)alkyl; and R⁴⁹ represents (CH₂)₁₋₃—CO₂H, O(C₂-C₄)alkyl,(CH₂)₁₋₄—NR⁵⁰R⁵¹ wherein  R⁵⁰ and R⁵¹ independently represent H or(C₁-C₃)alkyl, or CH(R⁵²)—NR⁵³R⁵⁴ wherein  R⁵² represents (CH₂)₁₋₄—NH₂,CH₂OH, CH(CH₃)OH, or (C₁-C₃)alkyl; and  R⁵³ and R⁵⁴ independentlyrepresent H or (C₁-C₃)alkyl.
 5. The compound of claim 4 wherein R¹represents H; R² represents O(C₁-C₃)alkyl or NR³R⁴ wherein R³ and R⁴ areH or (C₁-C₃)alkyl; R^(2a) represents H; L represents O or CR⁶R⁷, whereinR⁶ and R⁷ are independently H, CH₃, or OH; G″ represents a substituentselected from the group consisting of O(C₁-C₃)alkyl, halogen, and CF₃; nand n′ are independently 0 or 1, and provisos 1-3 do not apply; G and G′moieties are independently selected from the group consisting of: G1) Clor F; G2) O(C₁-C₃)alkyl; G3) OH; G4) (C₁-C₃)alkyl, which is optionallysubstituted up to three times by halogen; G5) OCF₃; G8) NR¹⁰R¹¹, whereinR¹⁰ and R¹¹ are independently selected from H, CH₃, cyclopropyl, benzyl,NR¹²R¹³ wherein  R¹² and R¹³ are independently H or (C₁-C₃)alkyl,provided that both R¹⁰ and R¹¹ are not NR¹²R¹³ simultaneously, and(C₂-C₄)alkyl which is optionally substituted up to three times byhalogen, and up to two times by substituent groups independentlyselected from hydroxyl, O(C₁-C₃)alkyl, and NR¹⁴R¹⁵, wherein  R¹⁴ and R¹⁵are independently H or (C₁-C₃)alkyl, or  R¹⁴ and R¹⁵ can join to form aheterocycle of formula

 wherein  Q represents CH₂, O, or NR¹⁶, and  R¹⁶ represents H or(C₁-C₃)alkyl, G12) OSO₂NR²³R²⁴ wherein R²³ and R²⁴ independentlyrepresent H, CH₃, or (C₂-C₄)alkyl which may optionally be substitutedonce by OH or NR²⁵R²⁶, wherein R²⁵ and R²⁶ independently represent H or(C₁-C₃)alkyl; G21) C(O)NR²⁸R²⁹, wherein R²⁸ and R²⁹ are independentlyselected from H and (C₁-C₃)alkyl which is optionally substituted up totwo times by OH; G25)

 wherein Q^(iv) is O or NR³⁴; and R³⁴ is H or (C₁-C₃)alkyl; G26)C(O)NR³⁵(CH₂)_(f)OR³⁶ wherein R³⁵ is H or (C₁-C₃)alkyl; R³⁶ is(C₁-C₆)alkyl optionally substituted up to two times by halogen, OH, orO(C₁-C₃)alkyl, and the subscript “f” is an integer of 2-4; and G31)N(R⁴⁸)C(O)R⁴⁹ wherein R⁴⁸ represents H or (C₁-C₃)alkyl; and R⁴⁹represents (CH₂)₁₋₃—CO₂H, O(C₂-C₄)alkyl, (CH₂)₁₋₄—NR⁵⁰R⁵¹ wherein  R⁵⁰and R⁵¹ independently represent H or (C₁-C₃)alkyl, or CH(R⁵²)—NR⁵³R⁵⁴wherein  R⁵² represents (CH₂)₁₋₄—NH₂, CH₂OH, CH(CH₃)OH, or (C₁-C₃)alkyl;and  R⁵³ and R⁵⁴ independently represent H or (C₁-C₃)alkyl.
 6. Thecompound of claim 1 wherein R¹ represents H; M represents CH; Jrepresents an aromatic or heteroaromatic ring selected from the groupconsisting of

Y represents an aromatic or heteroaromatic ring selected from the groupconsisting of

n and n′ are independently 0, 1, 2, or 3, subject to the provisosthat 1) ring J and ring Y each may be substituted independently up to 3times by substituents listed below as numbers G1-G2, to a maximum totalof 4 substituents on rings J and Y, 2) ring J and ring Y each may besubstituted independently up to 2 times by substituents listed below asnumbers G3-G5 and G8, to a maximum total of 3 substituents on rings Jand Y, and 3) ring J and ring Y each may be substituted independentlyonce by a substituent selected from those listed below as numbers G12,G22, and G31; and subject to the further proviso 4) when J is pyridyl, nis 1, 2, or 3; and proviso 5 does not apply; G and G′ moieties areindependently selected from the group consisting of: G1) halogen; G2)O(C₁-C₄)alkyl which optionally is substituted up to two times byO(C₁-C₂)alkyl; G3) OH; G4) (C₁-C₅)alkyl, which is optionally substitutedindependently up to two times by groups selected from hydroxyl andcyano, or up to three times by halogen; G5) OCF₃; G8) NR¹⁰R¹¹, whereinR¹⁰ and R¹¹ are independently selected from H, CH₃, cyclopropyl, benzyl,NR¹²R¹³ wherein  R¹² and R¹³ are independently H or (C₁-C₃)alkyl,provided that both R¹⁰ and R¹¹ are not NR¹²R¹³ simultaneously, and(C₂-C₄)alkyl which is optionally substituted up to three times byhalogen, and up to two times by substituent groups independentlyselected from hydroxyl, O(C₁-C₃)alkyl, and NR¹⁴R¹⁵, wherein  R¹⁴ and R¹⁵are independently H or (C₁-C₃)alkyl, or  R¹⁴ and R¹⁵ can join to form aheterocycle of formula

 wherein  Q represents CH₂, O, or NR¹⁶, and  R¹⁶ represents H or(C₁-C₃)alkyl, or R¹⁰ and R¹¹ may be joined to form a saturated5-6-membered N-containing ring which is optionally substituted up to twotimes by OH, NR¹⁷R¹⁸, wherein  R¹⁷ and R¹⁸ are H or (C₁-C₃)alkyl, or by(C₁-C₃)alkyl which is optionally substituted up to two times by halogen,OH, or O(C₁-C₃)alkyl; G12) OSO₂NR²³R²⁴ wherein R²³ and R²⁴ independentlyrepresent H, CH₃, or (C₂-C₄)alkyl which may optionally be substitutedonce by OH or NR²⁵R²⁶ wherein R²⁵ and R²⁶ independently represent H or(C₁-C₃)alkyl; G22)

 wherein Q″ is O or NR³⁰, and R³⁰ is H, cyclopropyl, or (C₁-C₃)alkylwhich is optionally substituted once by halogen, OH, or O(C₁-C₃)alkyl;and G31) N(R⁴⁸)C(O)R⁴⁹ wherein R⁴⁸ represents H or (C₁-C₃)alkyl; and R⁴⁹represents (CH₂)₁₋₃—CO₂H, O(C₂-C₄)alkyl, (CH₂)₁₋₄—NR⁵⁰R⁵¹ wherein  R⁵⁰and R⁵¹ independently represent H or (C₁-C₃)alkyl, or CH(R⁵²)—NR⁵³R⁵⁴wherein  R⁵² represents (CH₂)₁₋₄—NH₂, CH₂OH, CH(CH₃)OH, or (C₁-C₃)alkyl;and  R⁵³ and R⁵⁴ independently represent H or (C₁-C₃)alkyl.
 7. Thecompound of claim 6 wherein R¹ represents H; R² representsO(C₁-C₃)alkyl, or NR³R⁴ wherein R³ and R⁴ are H or (C₁-C₃)alkyl; R^(2a)represents H; L represents O or CR⁶R⁷, wherein R⁶ and R⁷ areindependently H, CH₃, or OH; G″ represents a substituent selected fromthe group consisting of O(C₁-C₃)alkyl, halogen, and CF₃; n and n′ areindependently 0 or 1, and provisos 1-3 do not apply; G and G′ moietiesare independently selected from the group consisting of: G1) Cl or F;G2) O(C₁-C₃)alkyl; G3) OH; G4) (C₁-C₃)alkyl, which is optionallysubstituted up to three times by halogen; G5) OCF₃; G8) NR¹⁰R¹¹, whereinR¹⁰ and R¹¹ are independently selected from H, CH₃, cyclopropyl, benzyl,NR¹²R¹³ wherein  R¹² and R¹³ are independently H or (C₁-C₃)alkyl,provided that both R¹⁰ and R¹¹ are not NR¹²R¹³ simultaneously, and(C₂-C₄)alkyl which is optionally substituted up to three times byhalogen, and up to two times by substituent groups independentlyselected from hydroxyl, O(C₁-C₃)alkyl, and NR¹⁴R¹⁵, wherein  R¹⁴ and R¹⁵are independently H or C₁-C₃)alkyl, or  R¹⁴ and R¹⁵ can join to form aheterocycle of formula

 wherein  Q represents CH₂, O, or NR¹⁶, and  R¹⁶ represents H or(C₁-C₃)alkyl; G12) OSO₂NR²³R²⁴ wherein R²³ and R²⁴ independentlyrepresent H, CH₃, or (C₂-C₄)alkyl which may optionally be substitutedonce by OH or NR²⁵R²⁶, wherein R²⁵ and R²⁶ independently represent H or(C₁-C₃)alkyl; G22)

 wherein Q″ is O or NR³⁰, and R³⁰ is H or (C₁-C₃)alkyl; and G31)N(R⁴⁸)C(O)R⁴⁹ wherein R⁴⁸ represents H or (C₁-C₃)alkyl; and R⁴⁹represents (CH₂)₁₋₃—CO₂H, O(C₂-C₄)alkyl, (CH₂)₁₋₄—NR⁵⁰R⁵¹ wherein  R⁵⁰and R⁵¹ independently represent H or (C₁-C₃)alkyl, or CH(R⁵²)—NR⁵³R⁵⁴wherein  R⁵² represents (CH₂)₁₋₄—NH₂, CH₂OH, CH(CH₃)OH, or (C₁-C₃)alkyl;and  R⁵³ and R⁵⁴ independently represent H or (C₁-C₃)alkyl.
 8. Acompound selected from the group consisting of4-{3-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}-N-methylpyridine-2-carboxamide;4-{3-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxamide;4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carbonitrile;6-phenyl-N⁴-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine;N⁴-{4-[(2-chloropyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine;4-{2-amino-6-[(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}phenylsulfamate;N-(4-{2-amino-6-[(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}-phenyl)amino]pyrimidin-4-yl}phenyl)glycinamidetrifluoroacetate;6-(4-aminophenyl)-N⁴-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine;6-(6-aminopyridin-3-yl)-N⁴-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine;6-pyridin-3-yl-N⁴-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}-phenyl)pyrimidine-2,4-diamine;N-[(4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl]-4-methoxybenzenesulfonamidetrifluoroacetate;N-[(4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl]methanesulfonamidetrifluoroacetate; and(4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methanoltrifluoroacetate (salt).
 9. A compound of selected from the groupconsisting of(6-(2,6-dimethylphenyl)-N⁴-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine)

(6-(6-aminopyridin-3-yl)-N⁴-{4-[(2-methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine)

(N⁶-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)-4,5′-bipyrimidine-2,6-diamine)

(6-phenyl-N⁴-(4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine)

and(6-(6-aminopyridin-3-yl)-N⁴-(4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine)


10. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 11. A method of treatment for ahyperproliferative disorder comprising administering an effective amountof a compound of claim 1 to a subject in need thereof.
 12. The method ofclaim 10 wherein said hyperproliferative disorder is cancer.
 13. Apackaged pharmaceutical composition comprising a container comprisingthe pharmaceutical composition of claim 10 and instructions for usingthe pharmaceutical composition to treat a disease or condition in amammal.
 14. The packaged pharmaceutical composition of claim 13, whereinthe disease or condition is cancer.